Advertisement

Role of Inflammatory Cytokines in the Initiation and Progression of Pancreatic Cancer

  • Madanraj Appiya SantharamEmail author
  • Vignesh Dhandapani
Chapter

Abstract

It is essential to identify different targets for pancreatic cancer (PC) as it is asymptomatic until it has metastasized to other organs. After which time, the convention methods to control cancer such as surgery and chemotherapy is no longer an option. Over the years, it has been noted that the inflammation is a major cause of initiation of pancreatitis, leading to cancer. Various inflammatory cytokines initiate and play a role in progression of this cancer. In this chapter, we will be discussing about major inflammatory cytokines that have been identified over the years. For each cytokine, we will be looking at the source of the cytokines, the signaling mechanism of that cytokine, its role in other cancers followed by pancreatic cancer. Since the survival of many diagnosed PC patients are limited to months, understanding the origins and basic cascades of these different cytokines could better help in identifying the targets and developing different therapeutic approaches in screening of the patients with this disease.

Keywords

Cytokines Pancreatic Cancer Inflammation Extra-cellular Matrix Interleukins 

Abbreviations

AP-1

Activating Protein 1

APC

Antigen Presenting Cells

ASK

Apoptosis Signal-regulating Kinase

BAD

BCL2 Associated Death Promoter

BMP

Bone Morphogenetic Protein

CAF

Cancer Associated Fibroblasts

CD

Cluster of Differentiation

CLC

Cardiotrophin-Like Cytokine

CNTF

Ciliary Neurotrophic Factor

DC

Dendritic Cells

ECM

Extra Cellular Matrix

EMT

Epithelial-Mesenchymal Transition

ERK

Extracellular Signal-Regulated Kinases

FADD

Fas-Associated protein with Death Domain

GDF

Growth and Differentiation Factors

GDNF

Glial cell line-Derived Neurotrophic Factor

GM-CSF

Granulocyte Macrophage Colony Stimulating Factor

IFN

Interferon

IKK

IκB Kinase

IL

Interleukin

JAK

Janus Kinase

JNK

c-Jun N-terminal Kinase

LAP

Latency-Associated Peptide

LIF

Leukemia Inhibitory Factory

LLC

Large Latent Complex

LTBP

Latent TGF-β Binding Proteins

MAPK/MEK

Mitogen Activated Protein Kinases

MDSC

Myeloid Derived Suppressor Cells

MHC

Major Histocompatibility Complex

MLK

Mixed-Lineage Protein Kinases

MMP

Matrix Metalloproteinase

NF-κB

Nuclear Factor-κB

NK

Natural Killer

OSM

Oncostatin M

PanIN

Pancreatic Intraepithelial Neoplasia

PDAC

Pancreatic Ductal Adenocarcinoma

PI3K

Phosphoinositide 3-Kinase

PSC

Pancreatic Stellate Cells

PTEN

Phosphatase and Tensin Homolog

RAGE

Receptor for Advanced Glycation End products

RIP

Receptor Interacting Protein

ROS

Reactive Oxygen Species

RTK

Receptor Tyrosine Kinase

SBE

STAT Binding Elements

SCID

Severe Combined Immunodeficiency

SMA

Smooth Muscle Actin

SMAD

Small Mothers Against Decapentaplegic

SOCS

Suppressor of Cytokine Signaling

SODD

Silencer of Death Domain protein

SRF

Serum Response Factor

STAT

Signal Transducer and Activator of Transcription

TAK

TGF-β-Activated Kinase

TGF

Transforming Growth Factor

TME

Tumor Microenvironment

TNF

Tumor Necrosis Factor

TRADD

TNF Receptor-Associated Death Domain protein

TRAF

TNF Receptor-Associated Factor

Tregs

Regulatory T-cells

Tyk

Tyrosine Kinase

VEGF

Vascular Endothelial Growth Factor

References

  1. 1.
    Aldaz CM, Ferguson BW, Abba MC (2014) WWOX at the crossroads of cancer, metabolic syndrome related traits and CNS pathologies. Biochim Biophys Acta 1846(1):188–200.  https://doi.org/10.1016/j.bbcan.2014.06.001CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Anderson CF, Oukka M, Kuchroo VJ, Sacks D (2007) CD4(+)CD25(-)Foxp3(-) Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis. J Exp Med 204(2):285–297.  https://doi.org/10.1084/jem.20061886CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Ando K, Takahashi F, Motojima S, Nakashima K, Kaneko N, Hoshi K, Takahashi K (2013) Possible role for tocilizumab, an anti-interleukin-6 receptor antibody, in treating cancer cachexia. J Clin Oncol 31(6):e69–e72.  https://doi.org/10.1200/JCO.2012.44.2020CrossRefPubMedGoogle Scholar
  4. 4.
    Annes JP, Munger JS, Rifkin DB (2003) Making sense of latent TGFbeta activation. J Cell Sci 116(Pt 2):217–224CrossRefGoogle Scholar
  5. 5.
    Anzano MA, Roberts AB, Meyers CA, Komoriya A, Lamb LC, Smith JM, Sporn MB (1982) Synergistic interaction of two classes of transforming growth factors from murine sarcoma cells. Cancer Res 42(11):4776–4778PubMedGoogle Scholar
  6. 6.
    Askling J, Fahrbach K, Nordstrom B, Ross S, Schmid CH, Symmons D (2011) Cancer risk with tumor necrosis factor alpha (TNF) inhibitors: meta-analysis of randomized controlled trials of adalimumab, etanercept, and infliximab using patient level data. Pharmacoepidemiol Drug Saf 20(2):119–130.  https://doi.org/10.1002/pds.2046CrossRefPubMedGoogle Scholar
  7. 7.
    Aykul S, Martinez-Hackert E (2016) Transforming Growth Factor-beta Family Ligands Can Function as Antagonists by Competing for Type II Receptor Binding. J Biol Chem 291(20):10792–10804.  https://doi.org/10.1074/jbc.M115.713487CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Baeyens KJ, De Bondt HL, Raeymaekers A, Fiers W, De Ranter CJ (1999) The structure of mouse tumour-necrosis factor at 1.4 A resolution: towards modulation of its selectivity and trimerization. Acta Crystallogr D Biol Crystallogr 55(Pt 4):772–778CrossRefGoogle Scholar
  9. 9.
    Balkwill F (2009) Tumour necrosis factor and cancer. Nat Rev Cancer 9(5):361–371.  https://doi.org/10.1038/nrc2628CrossRefPubMedGoogle Scholar
  10. 10.
    Bao B, Ali S, Ahmad A, Azmi AS, Li Y, Banerjee S et al (2012) Hypoxia-induced aggressiveness of pancreatic cancer cells is due to increased expression of VEGF, IL-6 and miR-21, which can be attenuated by CDF treatment. PLoS One 7(12):e50165.  https://doi.org/10.1371/journal.pone.0050165CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Barry SP, Davidson SM, Townsend PA (2008) Molecular regulation of cardiac hypertrophy. Int J Biochem Cell Biol 40(10):2023–2039.  https://doi.org/10.1016/j.biocel.2008.02.020CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Batchu RB, Gruzdyn OV, Mahmud EM, Chukr F, Dachepalli R, Manmari SK et al (2018) Inhibition of Interleukin-10 in the tumor microenvironment can restore mesothelin chimeric antigen receptor T cell activity in pancreatic cancer in vitro. Surgery 163(3):627–632.  https://doi.org/10.1016/j.surg.2017.10.056CrossRefPubMedGoogle Scholar
  13. 13.
    Bellone G, Carbone A, Smirne C, Scirelli T, Buffolino A, Novarino A et al (2006) Cooperative induction of a tolerogenic dendritic cell phenotype by cytokines secreted by pancreatic carcinoma cells. J Immunol 177(5):3448–3460CrossRefGoogle Scholar
  14. 14.
    Bellone G, Smirne C, Mauri FA, Tonel E, Carbone A, Buffolino A et al (2006) Cytokine expression profile in human pancreatic carcinoma cells and in surgical specimens: implications for survival. Cancer Immunol Immunother 55(6):684–698.  https://doi.org/10.1007/s00262-005-0047-0CrossRefPubMedGoogle Scholar
  15. 15.
    Benzel J, Fendrich V (2018) Familial Pancreatic Cancer. Oncol Res Treat 41(10):611–618.  https://doi.org/10.1159/000493473CrossRefPubMedGoogle Scholar
  16. 16.
    Berlato C, Cassatella MA, Kinjyo I, Gatto L, Yoshimura A, Bazzoni F (2002) Involvement of suppressor of cytokine signaling-3 as a mediator of the inhibitory effects of IL-10 on lipopolysaccharide-induced macrophage activation. J Immunol 168(12):6404–6411CrossRefGoogle Scholar
  17. 17.
    Berti FCB, Pereira APL, Cebinelli GCM, Trugilo KP, Brajao de Oliveira K (2017) The role of interleukin 10 in human papilloma virus infection and progression to cervical carcinoma. Cytokine Growth Factor Rev 34:1–13.  https://doi.org/10.1016/j.cytogfr.2017.03.002CrossRefPubMedGoogle Scholar
  18. 18.
    Black RA, Rauch CT, Kozlosky CJ, Peschon JJ, Slack JL, Wolfson MF et al (1997) A metalloproteinase disintegrin that releases tumour-necrosis factor-alpha from cells. Nature 385(6618):729–733.  https://doi.org/10.1038/385729a0CrossRefPubMedGoogle Scholar
  19. 19.
    Blogowski W, Deskur A, Budkowska M, Salata D, Madej-Michniewicz A, Dabkowski K et al (2014) Selected cytokines in patients with pancreatic cancer: a preliminary report. PLoS One 9(5):e97613.  https://doi.org/10.1371/journal.pone.0097613CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Bulek K, Liu C, Swaidani S, Wang L, Page RC, Gulen MF et al (2011) The inducible kinase IKKi is required for IL-17-dependent signaling associated with neutrophilia and pulmonary inflammation. Nat Immunol 12(9):844–852.  https://doi.org/10.1038/ni.2080CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Bynigeri RR, Jakkampudi A, Jangala R, Subramanyam C, Sasikala M, Rao GV et al (2017) Pancreatic stellate cell: Pandora’s box for pancreatic disease biology. World J Gastroenterol 23(3):382–405.  https://doi.org/10.3748/wjg.v23.i3.382CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cassatella MA, Gasperini S, Bovolenta C, Calzetti F, Vollebregt M, Scapini P et al (1999) Interleukin-10 (IL-10) selectively enhances CIS3/SOCS3 mRNA expression in human neutrophils: evidence for an IL-10-induced pathway that is independent of STAT protein activation. Blood 94(8):2880–2889CrossRefGoogle Scholar
  23. 23.
    Castro-Villegas C, Perez-Sanchez C, Escudero A, Filipescu I, Verdu M, Ruiz-Limon P et al (2015) Circulating miRNAs as potential biomarkers of therapy effectiveness in rheumatoid arthritis patients treated with anti-TNFalpha. Arthritis Res Ther 17:49.  https://doi.org/10.1186/s13075-015-0555-zCrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Chen G, Goeddel DV (2002) TNF-R1 signaling: a beautiful pathway. Science 296(5573):1634–1635.  https://doi.org/10.1126/science.1071924CrossRefGoogle Scholar
  25. 25.
    Chen X, Tian J, Su GH, Lin J (2018) Blocking IL-6/GP130 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity in human pancreatic cancer cells. Curr Cancer Drug Targets.  https://doi.org/10.2174/1568009618666180430123939CrossRefGoogle Scholar
  26. 26.
    Chen Y, Ayaru L, Mathew S, Morris E, Pereira SP, Behboudi S (2014) Expansion of anti-mesothelin specific CD4+ and CD8+ T cell responses in patients with pancreatic carcinoma. PLoS One 9(2):e88133.  https://doi.org/10.1371/journal.pone.0088133CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cheng H, Fan K, Luo G, Fan Z, Yang C, Huang Q et al (2019) Kras(G12D) mutation contributes to regulatory T cell conversion through activation of the MEK/ERK pathway in pancreatic cancer. Cancer Lett 446:103–111.  https://doi.org/10.1016/j.canlet.2019.01.013CrossRefPubMedGoogle Scholar
  28. 28.
    Chow JY, Ban M, Wu HL, Nguyen F, Huang M, Chung H et al (2010) TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol 298(2):G275–G282.  https://doi.org/10.1152/ajpgi.00344.2009CrossRefPubMedGoogle Scholar
  29. 29.
    Ciechomska M, Bonek K, Merdas M, Zarecki P, Swierkot J, Gluszko P et al (2018) Changes in MiRNA-5196 Expression as a Potential Biomarker of Anti-TNF-alpha Therapy in Rheumatoid Arthritis and Ankylosing Spondylitis Patients. Arch Immunol Ther Exp (Warsz) 66(5):389–397.  https://doi.org/10.1007/s00005-018-0513-yCrossRefGoogle Scholar
  30. 30.
    Corcoran RB, Contino G, Deshpande V, Tzatsos A, Conrad C, Benes CH et al (2011) STAT3 plays a critical role in KRAS-induced pancreatic tumorigenesis. Cancer Res 71(14):5020–5029.  https://doi.org/10.1158/0008-5472.CAN-11-0908CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Couper KN, Blount DG, Riley EM (2008) IL-10: the master regulator of immunity to infection. J Immunol 180(9):5771–5777CrossRefGoogle Scholar
  32. 32.
    Daley D, Zambirinis CP, Seifert L, Akkad N, Mohan N, Werba G et al (2016) γδ T cells support pancreatic oncogenesis by restraining αβ T cell activation. Cell 166(6):1485–1499. e1415CrossRefGoogle Scholar
  33. 33.
    Demangel C, Bertolino P, Britton WJ (2002) Autocrine IL-10 impairs dendritic cell (DC)-derived immune responses to mycobacterial infection by suppressing DC trafficking to draining lymph nodes and local IL-12 production. Eur J Immunol 32(4):994–1002.  https://doi.org/10.1002/1521-4141(200204)32:4<994::AID-IMMU994>3.0.CO;2-6CrossRefPubMedGoogle Scholar
  34. 34.
    DeSelm CJ, Tano ZE, Varghese AM, Adusumilli PS (2017) CAR T-cell therapy for pancreatic cancer. J Surg Oncol 116(1):63–74.  https://doi.org/10.1002/jso.24627CrossRefPubMedGoogle Scholar
  35. 35.
    Diakos CI, Charles KA, McMillan DC, Clarke SJ (2014) Cancer-related inflammation and treatment effectiveness. Lancet Oncol 15(11):e493–e503.  https://doi.org/10.1016/S1470-2045(14)70263-3CrossRefPubMedGoogle Scholar
  36. 36.
    Dickens LS, Powley IR, Hughes MA, MacFarlane M (2012) The ‘complexities’ of life and death: death receptor signalling platforms. Exp Cell Res 318(11):1269–1277.  https://doi.org/10.1016/j.yexcr.2012.04.005CrossRefPubMedGoogle Scholar
  37. 37.
    Dijkgraaf EM, Heusinkveld M, Tummers B, Vogelpoel LT, Goedemans R, Jha V et al (2013) Chemotherapy alters monocyte differentiation to favor generation of cancer-supporting M2 macrophages in the tumor microenvironment. Cancer Res 73(8):2480–2492.  https://doi.org/10.1158/0008-5472.CAN-12-3542CrossRefPubMedGoogle Scholar
  38. 38.
    Ding WX, Yin XM (2004) Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. J Cell Mol Med 8(4):445–454.  https://doi.org/10.1111/j.1582-4934.2004.tb00469.xCrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Ding Y, Chen D, Tarcsafalvi A, Su R, Qin L, Bromberg JS (2003) Suppressor of cytokine signaling 1 inhibits IL-10-mediated immune responses. J Immunol 170(3):1383–1391CrossRefGoogle Scholar
  40. 40.
    Dranoff G (2004) Cytokines in cancer pathogenesis and cancer therapy. Nat Rev Cancer 4(1):11–22.  https://doi.org/10.1038/nrc1252CrossRefPubMedGoogle Scholar
  41. 41.
    Dunn GP, Bruce AT, Ikeda H, Old LJ, Schreiber RD (2002) Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol 3(11):991–998.  https://doi.org/10.1038/ni1102-991CrossRefPubMedGoogle Scholar
  42. 42.
    Ebihara N, Matsuda A, Nakamura S, Matsuda H, Murakami A (2011) Role of the IL-6 classic- and trans-signaling pathways in corneal sterile inflammation and wound healing. Invest Ophthalmol Vis Sci 52(12):8549–8557.  https://doi.org/10.1167/iovs.11-7956CrossRefPubMedGoogle Scholar
  43. 43.
    Ebrahimi B, Tucker SL, Li D, Abbruzzese JL, Kurzrock R (2004) Cytokines in pancreatic carcinoma: correlation with phenotypic characteristics and prognosis. Cancer 101(12):2727–2736.  https://doi.org/10.1002/cncr.20672CrossRefPubMedGoogle Scholar
  44. 44.
    Egberts JH, Cloosters V, Noack A, Schniewind B, Thon L, Klose S et al (2008) Anti-tumor necrosis factor therapy inhibits pancreatic tumor growth and metastasis. Cancer Res 68(5):1443–1450.  https://doi.org/10.1158/0008-5472.CAN-07-5704CrossRefPubMedGoogle Scholar
  45. 45.
    Ellenrieder V, Buck A, Harth A, Jungert K, Buchholz M, Adler G et al (2004) KLF11 mediates a critical mechanism in TGF-beta signaling that is inactivated by Erk-MAPK in pancreatic cancer cells. Gastroenterology 127(2):607–620CrossRefGoogle Scholar
  46. 46.
    Ellenrieder V, Hendler SF, Ruhland C, Boeck W, Adler G, Gress TM (2001) TGF-beta-induced invasiveness of pancreatic cancer cells is mediated by matrix metalloproteinase-2 and the urokinase plasminogen activator system. Int J Cancer 93(2):204–211.  https://doi.org/10.1002/ijc.1330CrossRefPubMedGoogle Scholar
  47. 47.
    Feng L, Qi Q, Wang P, Chen H, Chen Z, Meng Z, Liu L (2018) Serum levels of IL-6, IL-8, and IL-10 are indicators of prognosis in pancreatic cancer. J Int Med Res 46(12):5228–5236.  https://doi.org/10.1177/0300060518800588CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Feng M, Xiong G, Cao Z, Yang G, Zheng S, Song X et al (2017) PD-1/PD-L1 and immunotherapy for pancreatic cancer. Cancer Lett 407:57–65.  https://doi.org/10.1016/j.canlet.2017.08.006CrossRefPubMedGoogle Scholar
  49. 49.
    Feurino LW, Fisher WE, Bharadwaj U, Yao Q, Chen C, Li M (2006) Current update of cytokines in pancreatic cancer: pathogenic mechanisms, clinical indication, and therapeutic values. Cancer Invest 24(7):696–703.  https://doi.org/10.1080/07357900600981398CrossRefPubMedGoogle Scholar
  50. 50.
    Feurino LW, Zhang Y, Bharadwaj U, Zhang R, Li F, Fisher WE et al (2007) IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells. Cancer Biol Ther 6(7):1096–1100CrossRefGoogle Scholar
  51. 51.
    Fiorentino DF, Bond MW, Mosmann TR (1989) Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J Exp Med 170(6):2081–2095.  https://doi.org/10.1084/jem.170.6.2081CrossRefPubMedGoogle Scholar
  52. 52.
    Fiorentino DF, Zlotnik A, Mosmann TR, Howard M, O’Garra A (1991) IL-10 inhibits cytokine production by activated macrophages. J Immunol 147(11):3815–3822Google Scholar
  53. 53.
    Foulds KE, Rotte MJ, Seder RA (2006) IL-10 is required for optimal CD8 T cell memory following Listeria monocytogenes infection. J Immunol 177(4):2565–2574CrossRefGoogle Scholar
  54. 54.
    Fujioka S, Nakamichi I, Esaki M, Asano K, Matsumoto T, Kitazono T (2014) Serum microRNA levels in patients with Crohn’s disease during induction therapy by infliximab. J Gastroenterol Hepatol 29(6):1207–1214.  https://doi.org/10.1111/jgh.12523CrossRefPubMedGoogle Scholar
  55. 55.
    Fukuda A, Wang SC, Morris JPT, Folias AE, Liou A, Kim GE et al (2011) Stat3 and MMP7 contribute to pancreatic ductal adenocarcinoma initiation and progression. Cancer Cell 19(4):441–455.  https://doi.org/10.1016/j.ccr.2011.03.002CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Funamizu N, Hu C, Lacy C, Schetter A, Zhang G, He P et al (2013) Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. Int J Cancer 132(4):785–794.  https://doi.org/10.1002/ijc.27736CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Gahring LC, Carlson NG, Kulmar RA, Rogers SW (1996) Neuronal expression of tumor necrosis factor alpha in the murine brain. Neuroimmunomodulation 3(5):289–303.  https://doi.org/10.1159/000097283CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Gao X, Cao Y, Yang W, Duan C, Aronson JF, Rastellini C et al (2013) BMP2 inhibits TGF-beta-induced pancreatic stellate cell activation and extracellular matrix formation. Am J Physiol Gastrointest Liver Physiol 304(9):G804–G813.  https://doi.org/10.1152/ajpgi.00306.2012CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Gaur U, Aggarwal BB (2003) Regulation of proliferation, survival and apoptosis by members of the TNF superfamily. Biochem Pharmacol 66(8):1403–1408CrossRefGoogle Scholar
  60. 60.
    Gilmore TD, Wolenski FS (2012) NF-kappaB: where did it come from and why? Immunol Rev 246(1):14–35.  https://doi.org/10.1111/j.1600-065X.2012.01096.xCrossRefPubMedGoogle Scholar
  61. 61.
    Giovarelli M, Musiani P, Modesti A, Dellabona P, Casorati G, Allione A et al (1995) Local release of IL-10 by transfected mouse mammary adenocarcinoma cells does not suppress but enhances antitumor reaction and elicits a strong cytotoxic lymphocyte and antibody-dependent immune memory. J Immunol 155(6):3112–3123PubMedGoogle Scholar
  62. 62.
    Gittler JK, Shemer A, Suarez-Farinas M, Fuentes-Duculan J, Gulewicz KJ, Wang CQ et al (2012) Progressive activation of T(H)2/T(H)22 cytokines and selective epidermal proteins characterizes acute and chronic atopic dermatitis. J Allergy Clin Immunol 130(6):1344–1354.  https://doi.org/10.1016/j.jaci.2012.07.012CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Harazono Y, Muramatsu T, Endo H, Uzawa N, Kawano T, Harada K et al (2013) miR-655 Is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. PLoS One 8(5):e62757.  https://doi.org/10.1371/journal.pone.0062757CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Hawa Z, Haque I, Ghosh A, Banerjee S, Harris L, Banerjee SK (2016) The miRacle in pancreatic cancer by miRNAs: tiny angels or devils in disease progression. Int J Mol Sci 17(6).  https://doi.org/10.3390/ijms17060809CrossRefGoogle Scholar
  65. 65.
    Hayden MS, Ghosh S (2014) Regulation of NF-kappaB by TNF family cytokines. Semin Immunol 26(3):253–266.  https://doi.org/10.1016/j.smim.2014.05.004CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Heinrich PC, Behrmann I, Muller-Newen G, Schaper F, Graeve L (1998) Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J 334(Pt 2):297–314.  https://doi.org/10.1042/bj3340297CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Heldin CH, Vanlandewijck M, Moustakas A (2012) Regulation of EMT by TGFbeta in cancer. FEBS Lett 586(14):1959–1970.  https://doi.org/10.1016/j.febslet.2012.02.037CrossRefPubMedGoogle Scholar
  68. 68.
    Herjan T, Yao P, Qian W, Li X, Liu C, Bulek K et al (2013) HuR is required for IL-17-induced Act1-mediated CXCL1 and CXCL5 mRNA stabilization. J Immunol 191(2):640–649.  https://doi.org/10.4049/jimmunol.1203315CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Herreros-Villanueva M, Hijona E, Cosme A, Bujanda L (2012) Mouse models of pancreatic cancer. World J Gastroenterol 18(12):1286–1294.  https://doi.org/10.3748/wjg.v18.i12.1286CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Hofmann MA, Kiecker F, Zuberbier T (2016) A systematic review of the role of interleukin-17 and the interleukin-20 family in inflammatory allergic skin diseases. Curr Opin Allergy Clin Immunol 16(5):451–457.  https://doi.org/10.1097/ACI.0000000000000310CrossRefPubMedGoogle Scholar
  71. 71.
    Holmer R, Goumas FA, Waetzig GH, Rose-John S, Kalthoff H (2014) Interleukin-6: a villain in the drama of pancreatic cancer development and progression. Hepatobiliary Pancreat Dis Int 13(4):371–380CrossRefGoogle Scholar
  72. 72.
    Huang C, Yang G, Jiang T, Huang K, Cao J, Qiu Z (2010) Effects of IL-6 and AG490 on regulation of Stat3 signaling pathway and invasion of human pancreatic cancer cells in vitro. J Exp Clin Cancer Res 29:51.  https://doi.org/10.1186/1756-9966-29-51CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Huang CK, Yang CY, Jeng YM, Chen CL, Wu HH, Chang YC et al (2014) Autocrine/paracrine mechanism of interleukin-17B receptor promotes breast tumorigenesis through NF-kappaB-mediated antiapoptotic pathway. Oncogene 33(23):2968–2977.  https://doi.org/10.1038/onc.2013.268CrossRefPubMedGoogle Scholar
  74. 74.
    Hymowitz SG, Filvaroff EH, Yin JP, Lee J, Cai L, Risser P et al (2001) IL-17s adopt a cystine knot fold: structure and activity of a novel cytokine, IL-17F, and implications for receptor binding. EMBO J 20(19):5332–5341.  https://doi.org/10.1093/emboj/20.19.5332CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Ikushima H, Miyazono K (2010) TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer 10(6):415–424.  https://doi.org/10.1038/nrc2853CrossRefPubMedGoogle Scholar
  76. 76.
    Jang JE, Hajdu CH, Liot C, Miller G, Dustin ML, Bar-Sagi D (2017) Crosstalk between regulatory T cells and tumor-associated dendritic cells negates anti-tumor immunity in pancreatic cancer. Cell Rep 20(3):558–571.  https://doi.org/10.1016/j.celrep.2017.06.062CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Javle M, Li Y, Tan D, Dong X, Chang P, Kar S, Li D (2014) Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. PLoS One 9(1):e85942.  https://doi.org/10.1371/journal.pone.0085942CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Johansson H, Andersson R, Bauden M, Hammes S, Holdenrieder S, Ansari D (2016) Immune checkpoint therapy for pancreatic cancer. World J Gastroenterol 22(43):9457–9476.  https://doi.org/10.3748/wjg.v22.i43.9457CrossRefPubMedPubMedCentralGoogle Scholar
  79. 79.
    Johnston FM, Tan MC, Tan BR Jr, Porembka MR, Brunt EM, Linehan DC et al (2009) Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer. Clin Cancer Res 15(21):6511–6518.  https://doi.org/10.1158/1078-0432.CCR-09-0565CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Josefowicz SZ, Lu LF, Rudensky AY (2012) Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 30:531–564.  https://doi.org/10.1146/annurev.immunol.25.022106.141623CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Joss A, Akdis M, Faith A, Blaser K, Akdis CA (2000) IL-10 directly acts on T cells by specifically altering the CD28 co-stimulation pathway. Eur J Immunol 30(6):1683–1690.  https://doi.org/10.1002/1521-4141(200006)30:6<1683::AID-IMMU1683>3.0.CO;2-ACrossRefPubMedGoogle Scholar
  82. 82.
    Kabashima A, Higuchi H, Takaishi H, Matsuzaki Y, Suzuki S, Izumiya M et al (2009) Side population of pancreatic cancer cells predominates in TGF-beta-mediated epithelial to mesenchymal transition and invasion. Int J Cancer 124(12):2771–2779.  https://doi.org/10.1002/ijc.24349CrossRefPubMedGoogle Scholar
  83. 83.
    Kang R, Loux T, Tang D, Schapiro NE, Vernon P, Livesey KM et al (2012) The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia. Proc Natl Acad Sci U S A 109(18):7031–7036.  https://doi.org/10.1073/pnas.1113865109CrossRefPubMedPubMedCentralGoogle Scholar
  84. 84.
    Kant S, Swat W, Zhang S, Zhang ZY, Neel BG, Flavell RA, Davis RJ (2011) TNF-stimulated MAP kinase activation mediated by a Rho family GTPase signaling pathway. Genes Dev 25(19):2069–2078.  https://doi.org/10.1101/gad.17224711CrossRefPubMedPubMedCentralGoogle Scholar
  85. 85.
    Karakhanova S, Link J, Heinrich M, Shevchenko I, Yang Y, Hassenpflug M et al (2015) Characterization of myeloid leukocytes and soluble mediators in pancreatic cancer: importance of myeloid-derived suppressor cells. Oncoimmunology 4(4):e998519.  https://doi.org/10.1080/2162402X.2014.998519CrossRefPubMedPubMedCentralGoogle Scholar
  86. 86.
    Kimura A, Naka T, Kishimoto T (2007) IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci U S A 104(29):12099–12104.  https://doi.org/10.1073/pnas.0705268104CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Klein AP, Brune KA, Petersen GM, Goggins M, Tersmette AC, Offerhaus GJ et al (2004) Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 64(7):2634–2638CrossRefGoogle Scholar
  88. 88.
    Krintel SB, Dehlendorff C, Hetland ML, Horslev-Petersen K, Andersen KK, Junker P et al (2016) Prediction of treatment response to adalimumab: a double-blind placebo-controlled study of circulating microRNA in patients with early rheumatoid arthritis. Pharmacogenomics J 16(2):141–146.  https://doi.org/10.1038/tpj.2015.30CrossRefPubMedGoogle Scholar
  89. 89.
    Landskron G, De la Fuente M, Thuwajit P, Thuwajit C, Hermoso MA (2014) Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014:149185.  https://doi.org/10.1155/2014/149185CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Lee J, Ho WH, Maruoka M, Corpuz RT, Baldwin DT, Foster JS et al (2001) IL-17E, a novel proinflammatory ligand for the IL-17 receptor homolog IL-17Rh1. J Biol Chem 276(2):1660–1664.  https://doi.org/10.1074/jbc.M008289200CrossRefPubMedGoogle Scholar
  91. 91.
    Lesina M, Kurkowski MU, Ludes K, Rose-John S, Treiber M, Kloppel G et al (2011) Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19(4):456–469.  https://doi.org/10.1016/j.ccr.2011.03.009CrossRefPubMedGoogle Scholar
  92. 92.
    Li MO, Wan YY, Sanjabi S, Robertson AK, Flavell RA (2006) Transforming growth factor-beta regulation of immune responses. Annu Rev Immunol 24:99–146.  https://doi.org/10.1146/annurev.immunol.24.021605.090737CrossRefPubMedGoogle Scholar
  93. 93.
    Liang S, Ristich V, Arase H, Dausset J, Carosella ED, Horuzsko A (2008) Modulation of dendritic cell differentiation by HLA-G and ILT4 requires the IL-6--STAT3 signaling pathway. Proc Natl Acad Sci U S A 105(24):8357–8362.  https://doi.org/10.1073/pnas.0803341105CrossRefPubMedPubMedCentralGoogle Scholar
  94. 94.
    Loncle C, Bonjoch L, Folch-Puy E, Lopez-Millan MB, Lac S, Molejon MI et al (2015) IL17 functions through the novel REG3beta-JAK2-STAT3 inflammatory pathway to promote the transition from chronic pancreatitis to pancreatic cancer. Cancer Res 75(22):4852–4862.  https://doi.org/10.1158/0008-5472.CAN-15-0896CrossRefPubMedPubMedCentralGoogle Scholar
  95. 95.
    Long KB, Tooker G, Tooker E, Luque SL, Lee JW, Pan X, Beatty GL (2017) IL6 Receptor Blockade Enhances Chemotherapy Efficacy in Pancreatic Ductal Adenocarcinoma. Mol Cancer Ther 16(9):1898–1908.  https://doi.org/10.1158/1535-7163.MCT-16-0899CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP, Gonzales-Crespo MR et al (2012) Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 308(9):898–908.  https://doi.org/10.1001/2012.jama.10857CrossRefPubMedGoogle Scholar
  97. 97.
    Lowenfels AB, Maisonneuve P, Cavallini G, Ammann RW, Lankisch PG, Andersen JR et al (1993) Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N Engl J Med 328(20):1433–1437.  https://doi.org/10.1056/NEJM199305203282001CrossRefPubMedGoogle Scholar
  98. 98.
    Maezawa Y, Nakajima H, Suzuki K, Tamachi T, Ikeda K, Inoue J et al (2006) Involvement of TNF receptor-associated factor 6 in IL-25 receptor signaling. J Immunol 176(2):1013–1018CrossRefGoogle Scholar
  99. 99.
    Mannino MH, Zhu Z, Xiao H, Bai Q, Wakefield MR, Fang Y (2015) The paradoxical role of IL-10 in immunity and cancer. Cancer Lett 367(2):103–107.  https://doi.org/10.1016/j.canlet.2015.07.009CrossRefPubMedGoogle Scholar
  100. 100.
    Markowitz J, Brooks TR, Duggan MC, Paul BK, Pan X, Wei L et al (2015) Patients with pancreatic adenocarcinoma exhibit elevated levels of myeloid-derived suppressor cells upon progression of disease. Cancer Immunol Immunother 64(2):149–159.  https://doi.org/10.1007/s00262-014-1618-8CrossRefPubMedGoogle Scholar
  101. 101.
    Masamune A, Yoshida N, Hamada S, Takikawa T, Nabeshima T, Shimosegawa T (2018) Exosomes derived from pancreatic cancer cells induce activation and profibrogenic activities in pancreatic stellate cells. Biochem Biophys Res Commun 495(1):71–77.  https://doi.org/10.1016/j.bbrc.2017.10.141CrossRefPubMedGoogle Scholar
  102. 102.
    Massague J (2012) TGFbeta signalling in context. Nat Rev Mol Cell Biol 13(10):616–630.  https://doi.org/10.1038/nrm3434CrossRefPubMedPubMedCentralGoogle Scholar
  103. 103.
    Masui T, Hosotani R, Doi R, Miyamoto Y, Tsuji S, Nakajima S et al (2002) Expression of IL-6 receptor in pancreatic cancer: involvement in VEGF induction. Anticancer Res 22(6C):4093–4100PubMedPubMedCentralGoogle Scholar
  104. 104.
    McAllister F, Bailey JM, Alsina J, Nirschl CJ, Sharma R, Fan H et al (2014) Oncogenic Kras activates a hematopoietic-to-epithelial IL-17 signaling axis in preinvasive pancreatic neoplasia. Cancer Cell 25(5):621–637.  https://doi.org/10.1016/j.ccr.2014.03.014CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    McAllister F, Leach SD (2014) Targeting IL-17 for pancreatic cancer prevention. Oncotarget 5(20):9530–9531.  https://doi.org/10.18632/oncotarget.2618CrossRefPubMedPubMedCentralGoogle Scholar
  106. 106.
    McCarroll JA, Naim S, Sharbeen G, Russia N, Lee J, Kavallaris M et al (2014) Role of pancreatic stellate cells in chemoresistance in pancreatic cancer. Front Physiol 5:141.  https://doi.org/10.3389/fphys.2014.00141CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Melisi D, Ishiyama S, Sclabas GM, Fleming JB, Xia Q, Tortora G et al (2008) LY2109761, a novel transforming growth factor beta receptor type I and type II dual inhibitor, as a therapeutic approach to suppressing pancreatic cancer metastasis. Mol Cancer Ther 7(4):829–840.  https://doi.org/10.1158/1535-7163.MCT-07-0337CrossRefPubMedPubMedCentralGoogle Scholar
  108. 108.
    Mitchell RE, Hassan M, Burton BR, Britton G, Hill EV, Verhagen J, Wraith DC (2017) IL-4 enhances IL-10 production in Th1 cells: implications for Th1 and Th2 regulation. Sci Rep 7(1):11315.  https://doi.org/10.1038/s41598-017-11803-yCrossRefPubMedPubMedCentralGoogle Scholar
  109. 109.
    Momi N, Kaur S, Krishn SR, Batra SK (2012) Discovering the route from inflammation to pancreatic cancer. Minerva Gastroenterol Dietol 58(4):283–297PubMedPubMedCentralGoogle Scholar
  110. 110.
    Mondragon L, Kroemer G, Galluzzi L (2016) Immunosuppressive gammadelta T cells foster pancreatic carcinogenesis. Oncoimmunology 5(11):e1237328.  https://doi.org/10.1080/2162402X.2016.1237328CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Moore KW, de Waal Malefyt R, Coffman RL, O’Garra A (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765.  https://doi.org/10.1146/annurev.immunol.19.1.683CrossRefPubMedGoogle Scholar
  112. 112.
    Nakamura K, Kitani A, Strober W (2001) Cell contact-dependent immunosuppression by CD4(+)CD25(+) regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 194(5):629–644.  https://doi.org/10.1084/jem.194.5.629CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Ni CW, Hsieh HJ, Chao YJ, Wang DL (2004) Interleukin-6-induced JAK2/STAT3 signaling pathway in endothelial cells is suppressed by hemodynamic flow. Am J Physiol Cell Physiol 287(3):C771–C780.  https://doi.org/10.1152/ajpcell.00532.2003CrossRefPubMedGoogle Scholar
  114. 114.
    Nicolas FJ, Hill CS (2003) Attenuation of the TGF-beta-Smad signaling pathway in pancreatic tumor cells confers resistance to TGF-beta-induced growth arrest. Oncogene 22(24):3698–3711.  https://doi.org/10.1038/sj.onc.1206420CrossRefPubMedGoogle Scholar
  115. 115.
    Novick D, Engelmann H, Wallach D, Rubinstein M (1989) Soluble cytokine receptors are present in normal human urine. J Exp Med 170(4):1409–1414.  https://doi.org/10.1084/jem.170.4.1409CrossRefPubMedGoogle Scholar
  116. 116.
    O’Garra A, Vieira P (2004) Regulatory T cells and mechanisms of immune system control. Nat Med 10(8):801–805.  https://doi.org/10.1038/nm0804-801CrossRefPubMedGoogle Scholar
  117. 117.
    O’Shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368(2):161–170.  https://doi.org/10.1056/NEJMra1202117CrossRefPubMedGoogle Scholar
  118. 118.
    Oeckinghaus A, Hayden MS, Ghosh S (2011) Crosstalk in NF-kappaB signaling pathways. Nat Immunol 12(8):695–708.  https://doi.org/10.1038/ni.2065CrossRefPubMedGoogle Scholar
  119. 119.
    Oida T, Weiner HL (2010) Overexpression of TGF-ss 1 gene induces cell surface localized glucose-regulated protein 78-associated latency-associated peptide/TGF-ss. J Immunol 185(6):3529–3535.  https://doi.org/10.4049/jimmunol.0904121CrossRefPubMedPubMedCentralGoogle Scholar
  120. 120.
    Olszewski MB, Groot AJ, Dastych J, Knol EF (2007) TNF trafficking to human mast cell granules: mature chain-dependent endocytosis. J Immunol 178(9):5701–5709CrossRefGoogle Scholar
  121. 121.
    Padua D, Massague J (2009) Roles of TGFbeta in metastasis. Cell Res 19(1):89–102.  https://doi.org/10.1038/cr.2008.316CrossRefPubMedGoogle Scholar
  122. 122.
    Palladino MA, Bahjat FR, Theodorakis EA, Moldawer LL (2003) Anti-TNF-alpha therapies: the next generation. Nat Rev Drug Discov 2(9):736–746.  https://doi.org/10.1038/nrd1175CrossRefPubMedGoogle Scholar
  123. 123.
    Pinho AV, Chantrill L, Rooman I (2014) Chronic pancreatitis: a path to pancreatic cancer. Cancer Lett 345(2):203–209.  https://doi.org/10.1016/j.canlet.2013.08.015CrossRefPubMedPubMedCentralGoogle Scholar
  124. 124.
    Pivarcsi A, Meisgen F, Xu N, Stahle M, Sonkoly E (2013) Changes in the level of serum microRNAs in patients with psoriasis after antitumour necrosis factor-alpha therapy. Br J Dermatol 169(3):563–570.  https://doi.org/10.1111/bjd.12381CrossRefPubMedGoogle Scholar
  125. 125.
    Qian Y, Liu C, Hartupee J, Altuntas CZ, Gulen MF, Jane-Wit D et al (2007) The adaptor Act1 is required for interleukin 17-dependent signaling associated with autoimmune and inflammatory disease. Nat Immunol 8(3):247–256.  https://doi.org/10.1038/ni1439CrossRefPubMedGoogle Scholar
  126. 126.
    Qu F, Gao H, Zhu S, Shi P, Zhang Y, Liu Y et al (2012) TRAF6-dependent Act1 phosphorylation by the IkappaB kinase-related kinases suppresses interleukin-17-induced NF-kappaB activation. Mol Cell Biol 32(19):3925–3937.  https://doi.org/10.1128/MCB.00268-12CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Ramirez-Carrozzi V, Sambandam A, Luis E, Lin Z, Jeet S, Lesch J et al (2011) IL-17C regulates the innate immune function of epithelial cells in an autocrine manner. Nat Immunol 12(12):1159–1166.  https://doi.org/10.1038/ni.2156CrossRefPubMedGoogle Scholar
  128. 128.
    Razidlo GL, Burton KM, McNiven MA (2018) Interleukin-6 promotes pancreatic cancer cell migration by rapidly activating the small GTPase CDC42. J Biol Chem 293(28):11143–11153.  https://doi.org/10.1074/jbc.RA118.003276CrossRefPubMedPubMedCentralGoogle Scholar
  129. 129.
    Rickel EA, Siegel LA, Yoon BR, Rottman JB, Kugler DG, Swart DA et al (2008) Identification of functional roles for both IL-17RB and IL-17RA in mediating IL-25-induced activities. J Immunol 181(6):4299–4310CrossRefGoogle Scholar
  130. 130.
    Rifkin DB (2005) Latent transforming growth factor-beta (TGF-beta) binding proteins: orchestrators of TGF-beta availability. J Biol Chem 280(9):7409–7412.  https://doi.org/10.1074/jbc.R400029200CrossRefPubMedGoogle Scholar
  131. 131.
    Ripka S, Konig A, Buchholz M, Wagner M, Sipos B, Kloppel G et al (2007) WNT5A--target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer. Carcinogenesis 28(6):1178–1187.  https://doi.org/10.1093/carcin/bgl255CrossRefPubMedGoogle Scholar
  132. 132.
    Rose-John S (2012) IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int J Biol Sci 8(9):1237–1247.  https://doi.org/10.7150/ijbs.4989CrossRefPubMedPubMedCentralGoogle Scholar
  133. 133.
    Rose-John S, Heinrich PC (1994) Soluble receptors for cytokines and growth factors: generation and biological function. Biochem J 300(Pt 2):281–290.  https://doi.org/10.1042/bj3000281CrossRefPubMedPubMedCentralGoogle Scholar
  134. 134.
    Rose-John S, Waetzig GH, Scheller J, Grotzinger J, Seegert D (2007) The IL-6/sIL-6R complex as a novel target for therapeutic approaches. Expert Opin Ther Targets 11(5):613–624.  https://doi.org/10.1517/14728222.11.5.613CrossRefPubMedGoogle Scholar
  135. 135.
    Roshani R, McCarthy F, Hagemann T (2014) Inflammatory cytokines in human pancreatic cancer. Cancer Lett 345(2):157–163.  https://doi.org/10.1016/j.canlet.2013.07.014CrossRefPubMedGoogle Scholar
  136. 136.
    Rouvier E, Luciani MF, Mattei MG, Denizot F, Golstein P (1993) CTLA-8, cloned from an activated T cell, bearing AU-rich messenger RNA instability sequences, and homologous to a herpesvirus saimiri gene. J Immunol 150(12):5445–5456PubMedGoogle Scholar
  137. 137.
    Saarma M (2000) GDNF – a stranger in the TGF-beta superfamily? Eur J Biochem 267(24):6968–6971CrossRefGoogle Scholar
  138. 138.
    Saraiva M, Christensen JR, Veldhoen M, Murphy TL, Murphy KM, O’Garra A (2009) Interleukin-10 production by Th1 cells requires interleukin-12-induced STAT4 transcription factor and ERK MAP kinase activation by high antigen dose. Immunity 31(2):209–219.  https://doi.org/10.1016/j.immuni.2009.05.012CrossRefPubMedPubMedCentralGoogle Scholar
  139. 139.
    Schandene L, Alonso-Vega C, Willems F, Gerard C, Delvaux A, Velu T et al (1994) B7/CD28-dependent IL-5 production by human resting T cells is inhibited by IL-10. J Immunol 152(9):4368–4374PubMedGoogle Scholar
  140. 140.
    Scheller J, Garbers C, Rose-John S (2014) Interleukin-6: from basic biology to selective blockade of pro-inflammatory activities. Semin Immunol 26(1):2–12.  https://doi.org/10.1016/j.smim.2013.11.002CrossRefPubMedGoogle Scholar
  141. 141.
    Schust J, Sperl B, Hollis A, Mayer TU, Berg T (2006) Stattic: a small-molecule inhibitor of STAT3 activation and dimerization. Chem Biol 13(11):1235–1242.  https://doi.org/10.1016/j.chembiol.2006.09.018CrossRefPubMedGoogle Scholar
  142. 142.
    Schwandner R, Yamaguchi K, Cao Z (2000) Requirement of tumor necrosis factor receptor-associated factor (TRAF)6 in interleukin 17 signal transduction. J Exp Med 191(7):1233–1240.  https://doi.org/10.1084/jem.191.7.1233CrossRefPubMedPubMedCentralGoogle Scholar
  143. 143.
    Shadhu K, Xi C (2019) Inflammation and pancreatic cancer: An updated review. Saudi J Gastroenterol 25(1):3–13.  https://doi.org/10.4103/sjg.SJG_390_18CrossRefPubMedPubMedCentralGoogle Scholar
  144. 144.
    Shah N, Kammermeier J, Elawad M, Glocker EO (2012) Interleukin-10 and interleukin-10-receptor defects in inflammatory bowel disease. Curr Allergy Asthma Rep 12(5):373–379.  https://doi.org/10.1007/s11882-012-0286-zCrossRefPubMedGoogle Scholar
  145. 145.
    Shek FW, Benyon RC, Walker FM, McCrudden PR, Pender SL, Williams EJ et al (2002) Expression of transforming growth factor-beta 1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis. Am J Pathol 160(5):1787–1798CrossRefGoogle Scholar
  146. 146.
    Shinriki S, Jono H, Ota K, Ueda M, Kudo M, Ota T et al (2009) Humanized anti-interleukin-6 receptor antibody suppresses tumor angiogenesis and in vivo growth of human oral squamous cell carcinoma. Clin Cancer Res 15(17):5426–5434.  https://doi.org/10.1158/1078-0432.CCR-09-0287CrossRefPubMedGoogle Scholar
  147. 147.
    Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68(1):7–30.  https://doi.org/10.3322/caac.21442CrossRefGoogle Scholar
  148. 148.
    Song X, Zhu S, Shi P, Liu Y, Shi Y, Levin SD, Qian Y (2011) IL-17RE is the functional receptor for IL-17C and mediates mucosal immunity to infection with intestinal pathogens. Nat Immunol 12(12):1151–1158.  https://doi.org/10.1038/ni.2155CrossRefPubMedGoogle Scholar
  149. 149.
    Sun D, Novotny M, Bulek K, Liu C, Li X, Hamilton T (2011) Treatment with IL-17 prolongs the half-life of chemokine CXCL1 mRNA via the adaptor TRAF5 and the splicing-regulatory factor SF2 (ASF). Nat Immunol 12(9):853–860.  https://doi.org/10.1038/ni.2081CrossRefPubMedPubMedCentralGoogle Scholar
  150. 150.
    Taga T, Kishimoto T (1997) Gp130 and the interleukin-6 family of cytokines. Annu Rev Immunol 15:797–819.  https://doi.org/10.1146/annurev.immunol.15.1.797CrossRefPubMedGoogle Scholar
  151. 151.
    Takano S, Kanai F, Jazag A, Ijichi H, Yao J, Ogawa H et al (2007) Smad4 is essential for down-regulation of E-cadherin induced by TGF-beta in pancreatic cancer cell line PANC-1. J Biochem 141(3):345–351.  https://doi.org/10.1093/jb/mvm039CrossRefPubMedGoogle Scholar
  152. 152.
    Tanaka T, Narazaki M, Kishimoto T (2014) IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a016295.  https://doi.org/10.1101/cshperspect.a016295CrossRefPubMedPubMedCentralGoogle Scholar
  153. 153.
    Tang RF, Wang SX, Zhang FR, Peng L, Wang SX, Xiao Y, Zhang M (2005) Interleukin-1alpha, 6 regulate the secretion of vascular endothelial growth factor A, C in pancreatic cancer. Hepatobiliary Pancreat Dis Int 4(3):460–463PubMedGoogle Scholar
  154. 154.
    Thannickal VJ, Fanburg BL (2000) Reactive oxygen species in cell signaling. Am J Physiol Lung Cell Mol Physiol 279(6):L1005–L1028.  https://doi.org/10.1152/ajplung.2000.279.6.L1005CrossRefPubMedGoogle Scholar
  155. 155.
    Theiss AL, Simmons JG, Jobin C, Lund PK (2005) Tumor necrosis factor (TNF) alpha increases collagen accumulation and proliferation in intestinal myofibroblasts via TNF receptor 2. J Biol Chem 280(43):36099–36109.  https://doi.org/10.1074/jbc.M505291200CrossRefPubMedGoogle Scholar
  156. 156.
    Trinchieri G (2007) Interleukin-10 production by effector T cells: Th1 cells show self control. J Exp Med 204(2):239–243.  https://doi.org/10.1084/jem.20070104CrossRefPubMedPubMedCentralGoogle Scholar
  157. 157.
    Vasseur P, Devaure I, Sellier J, Delwail A, Chagneau-Derrode C, Charier F et al (2014) High plasma levels of the pro-inflammatory cytokine IL-22 and the anti-inflammatory cytokines IL-10 and IL-1ra in acute pancreatitis. Pancreatology 14(6):465–469.  https://doi.org/10.1016/j.pan.2014.08.005CrossRefPubMedGoogle Scholar
  158. 158.
    Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G et al (1998) Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene 17(15):1969–1978.  https://doi.org/10.1038/sj.onc.1202118CrossRefPubMedGoogle Scholar
  159. 159.
    von Ahrens D, Bhagat TD, Nagrath D, Maitra A, Verma A (2017) The role of stromal cancer-associated fibroblasts in pancreatic cancer. J Hematol Oncol 10(1):76.  https://doi.org/10.1186/s13045-017-0448-5CrossRefGoogle Scholar
  160. 160.
    Wajant H, Pfizenmaier K, Scheurich P (2003) Tumor necrosis factor signaling. Cell Death Differ 10(1):45–65.  https://doi.org/10.1038/sj.cdd.4401189CrossRefPubMedGoogle Scholar
  161. 161.
    Waters JP, Pober JS, Bradley JR (2013) Tumour necrosis factor and cancer. J Pathol 230(3):241–248.  https://doi.org/10.1002/path.4188CrossRefPubMedGoogle Scholar
  162. 162.
    Wey JS, Gray MJ, Fan F, Belcheva A, McCarty MF, Stoeltzing O et al (2005) Overexpression of neuropilin-1 promotes constitutive MAPK signalling and chemoresistance in pancreatic cancer cells. Br J Cancer 93(2):233–241.  https://doi.org/10.1038/sj.bjc.6602663CrossRefPubMedPubMedCentralGoogle Scholar
  163. 163.
    Williams CJ, Peyrin-Biroulet L, Ford AC (2014) Systematic review with meta-analysis: malignancies with anti-tumour necrosis factor-alpha therapy in inflammatory bowel disease. Aliment Pharmacol Ther 39(5):447–458.  https://doi.org/10.1111/apt.12624CrossRefPubMedGoogle Scholar
  164. 164.
    Williams L, Bradley L, Smith A, Foxwell B (2004) Signal transducer and activator of transcription 3 is the dominant mediator of the anti-inflammatory effects of IL-10 in human macrophages. J Immunol 172(1):567–576CrossRefGoogle Scholar
  165. 165.
    Wipff PJ, Hinz B (2008) Integrins and the activation of latent transforming growth factor beta1 – an intimate relationship. Eur J Cell Biol 87(8-9):601–615.  https://doi.org/10.1016/j.ejcb.2008.01.012CrossRefPubMedGoogle Scholar
  166. 166.
    Wu L, Zepp JA, Qian W, Martin BN, Ouyang W, Yin W et al (2015) A novel IL-25 signaling pathway through STAT5. J Immunol 194(9):4528–4534.  https://doi.org/10.4049/jimmunol.1402760CrossRefPubMedPubMedCentralGoogle Scholar
  167. 167.
    Wu S, Rhee KJ, Albesiano E, Rabizadeh S, Wu X, Yen HR et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15(9):1016–1022.  https://doi.org/10.1038/nm.2015CrossRefPubMedPubMedCentralGoogle Scholar
  168. 168.
    Xing HB, Tong MT, Wang J, Hu H, Zhai CY, Huang CX, Li D (2018) Suppression of IL-6 gene by shRNA augments gemcitabine chemosensitization in pancreatic adenocarcinoma cells. Biomed Res Int 2018:3195025.  https://doi.org/10.1155/2018/3195025CrossRefPubMedPubMedCentralGoogle Scholar
  169. 169.
    Xu XF, Liu F, Xin JQ, Fan JW, Wu N, Zhu LJ et al (2018) Respective roles of the mitogen-activated protein kinase (MAPK) family members in pancreatic stellate cell activation induced by transforming growth factor-beta1 (TGF-beta1). Biochem Biophys Res Commun 501(2):365–373.  https://doi.org/10.1016/j.bbrc.2018.04.176CrossRefPubMedGoogle Scholar
  170. 170.
    Yagil Z, Nechushtan H, Kay G, Yang CM, Kemeny DM, Razin E (2010) The enigma of the role of protein inhibitor of activated STAT3 (PIAS3) in the immune response. Trends Immunol 31(5):199–204.  https://doi.org/10.1016/j.it.2010.01.005CrossRefPubMedGoogle Scholar
  171. 171.
    Yako YY, Kruger D, Smith M, Brand M (2016) Cytokines as biomarkers of pancreatic ductal adenocarcinoma: a systematic review. PLoS One 11(5):e0154016.  https://doi.org/10.1371/journal.pone.0154016CrossRefPubMedPubMedCentralGoogle Scholar
  172. 172.
    Yang Z, Ren F, Liu C, He S, Sun G, Gao Q et al (2010) dbDEMC: a database of differentially expressed miRNAs in human cancers. BMC Genomics 11(Suppl 4):S5.  https://doi.org/10.1186/1471-2164-11-S4-S5CrossRefPubMedPubMedCentralGoogle Scholar
  173. 173.
    Yao X, Huang J, Zhong H, Shen N, Faggioni R, Fung M, Yao Y (2014) Targeting interleukin-6 in inflammatory autoimmune diseases and cancers. Pharmacol Ther 141(2):125–139.  https://doi.org/10.1016/j.pharmthera.2013.09.004CrossRefPubMedGoogle Scholar
  174. 174.
    Yao Z, Fanslow WC, Seldin MF, Rousseau AM, Painter SL, Comeau MR et al (1995) Herpesvirus Saimiri encodes a new cytokine, IL-17, which binds to a novel cytokine receptor. Immunity 3(6):811–821CrossRefGoogle Scholar
  175. 175.
    Yao Z, Painter SL, Fanslow WC, Ulrich D, Macduff BM, Spriggs MK, Armitage RJ (1995) Human IL-17: a novel cytokine derived from T cells. J Immunol 155(12):5483–5486PubMedGoogle Scholar
  176. 176.
    Yu H, Pardoll D, Jove R (2009) STATs in cancer inflammation and immunity: a leading role for STAT3. Nat Rev Cancer 9(11):798–809.  https://doi.org/10.1038/nrc2734CrossRefPubMedPubMedCentralGoogle Scholar
  177. 177.
    Zepp JA, Wu L, Qian W, Ouyang W, Aronica M, Erzurum S, Li X (2015) TRAF4-SMURF2-mediated DAZAP2 degradation is critical for IL-25 signaling and allergic airway inflammation. J Immunol 194(6):2826–2837.  https://doi.org/10.4049/jimmunol.1402647CrossRefPubMedPubMedCentralGoogle Scholar
  178. 178.
    Zhang Y, Bharadwaj U, Logsdon CD, Chen C, Yao Q, Li M (2010) ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. Clin Cancer Res 16(5):1423–1430.  https://doi.org/10.1158/1078-0432.CCR-09-2405CrossRefPubMedPubMedCentralGoogle Scholar
  179. 179.
    Zhang Y, Yan W, Collins MA, Bednar F, Rakshit S, Zetter BR et al (2013) Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance. Cancer Res 73(20):6359–6374.  https://doi.org/10.1158/0008-5472.CAN-13-1558-TCrossRefPubMedGoogle Scholar
  180. 180.
    Zhang Y, Zoltan M, Riquelme E, Xu H, Sahin I, Castro-Pando S et al (2018) Immune cell production of interleukin 17 induces stem cell features of pancreatic intraepithelial neoplasia cells. Gastroenterology 155(1):210–223. e213.  https://doi.org/10.1053/j.gastro.2018.03.041CrossRefPubMedPubMedCentralGoogle Scholar
  181. 181.
    Zhao X, Fan W, Xu Z, Chen H, He Y, Yang G et al (2016) Inhibiting tumor necrosis factor-alpha diminishes desmoplasia and inflammation to overcome chemoresistance in pancreatic ductal adenocarcinoma. Oncotarget 7(49):81110–81122.  https://doi.org/10.18632/oncotarget.13212CrossRefPubMedPubMedCentralGoogle Scholar
  182. 182.
    Zrioual S, Ecochard R, Tournadre A, Lenief V, Cazalis MA, Miossec P (2009) Genome-wide comparison between IL-17A- and IL-17F-induced effects in human rheumatoid arthritis synoviocytes. J Immunol 182(5):3112–3120.  https://doi.org/10.4049/jimmunol.0801967CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Madanraj Appiya Santharam
    • 1
    Email author
  • Vignesh Dhandapani
    • 2
  1. 1.University of LeicesterLeicesterUK
  2. 2.Technische Universität DresdenDresdenGermany

Personalised recommendations