Abstract
Curcumin is a natural compound derived from the spice, turmeric, that has been extensively reported for its efficacy in controlling or treatment of several inflammatory diseases. There is a growing body of literature that recognizes the anti-inflammatory effects of curcumin in the immune system. On the other hand, the role of inflammatory signaling pathways has been highlighted in the pathogenesis of several inflammatory diseases, and signaling molecules involved in these pathways are considered as valuable targets for new treatment approaches. We aimed to provide a comprehensive overview of the modulatory effects of curcumin on inflammatory signaling pathways which leads to inhibition of inflammation in different types of immune cells and animal models. In this comprehensive review, we elaborate on how curcumin can effectively inhibit multiple signaling molecules involved in inflammation including NF-κB, JAKs/STATs, MAPKs, β-catenin, and Notch-1.
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Change history
19 August 2019
Unfortunately, the 4th author name was incorrectly published in the original article. The complete correct name is given below.
Abbreviations
- HSPs:
-
Heat shock proteins
- LPS:
-
Lipopolysaccharide
- DCs:
-
Dendritic cells
- TNF-α:
-
Tumor necrosis factor-α
- IL:
-
Interleukin
- IFN:
-
Interferon
- NF-κB:
-
Nuclear factor-κB
- JAK/STAT:
-
Janus kinase/signal transducer and activator of transcription
- MAPK:
-
Mitogen-activated protein kinase
- IBD:
-
Inflammatory bowel disease
- RA:
-
Rheumatoid arthritis
- SLE:
-
Systemic lupus erythematosus
- MS:
-
Multiple sclerosis
- T1DM:
-
Type 1 diabetes mellitus
- IκB:
-
Inhibitors of NF-κB
- IKK:
-
IκB kinase
- BMECs:
-
Brain microvascular endothelial cells
- HUVECs:
-
Human umbilical vein endothelial cells
- ICAM-1:
-
Intercellular adhesion molecule 1
- VCAM-1:
-
Vascular cell adhesion molecule 1
- MCP-1:
-
Monocyte chemoattractant protein-1
- PPARγ:
-
Peroxisome proliferator-activated receptor gamma
- iNOS:
-
Inducible nitric oxide synthase
- COX-2:
-
Cyclooxygenase-2
- SHP2:
-
Src homology 2 domain-containing protein tyrosine phosphatase
- OSM:
-
Oncostatin M
- MMP:
-
Matrix metalloproteinase
- EAE:
-
Experimental allergic encephalomyelitis
- RORγt:
-
RAR-related orphan receptor gamma
- TGF-β:
-
Transforming growth factor β
- SOCS:
-
Suppressor of cytokine signaling
- PIAS:
-
Protein inhibitor of activated STAT
- ERK:
-
Extracellular receptor-activated kinase
- JNK:
-
C-Jun N-terminal kinase
- PGE2:
-
Prostaglandin E2
- MPO:
-
Myeloperoxidase
- CMF:
-
Colonic myofibroblasts
- ROS:
-
Reactive oxygen species
- BBB:
-
Blood–brain barrier
- FLS:
-
Fibroblast-like synoviocyte
- LDH:
-
Lactate dehydrogenase
- OGD:
-
Oxygen–glucose deprivation
- GSK3:
-
Glycogen synthase kinase 3
- GATA3:
-
Transcription factor GATA binding protein 3
- TAK1:
-
Transforming growth factor (TGF)-activated kinase 1
- PMA:
-
Phorbol 12-myristate 13-acetate
- DLN:
-
Draining lymph node
- CRP:
-
C-reactive protein
- VEGF:
-
Vascular endothelial growth factor
References
Abdolahi M et al (2017) The synergistic effects of omega-3 fatty acids and nano-curcumin supplementation on tumor necrosis factor (TNF)-alpha gene expression and serum level in migraine patients. Immunogenetics 69:371–378. https://doi.org/10.1007/s00251-017-0992-8
Abdolahi M et al (2018) A novel combination of omega-3 fatty acids and nano-curcumin modulates interleukin-6 gene expression and high sensitivity C-reactive protein serum levels in patients with migraine: a randomized clinical trial study. CNS Neurol Disord Drug Targets 17:430–438. https://doi.org/10.2174/1871527317666180625101643
Abdolahi M et al (2019) The neuromodulatory effects of omega-3 fatty Acids and nano-curcumin on the COX-2/iNOS network in migraines: a clinical trial study from gene expression to clinical symptoms. Endocr Metab Immun Disord Drug Targets. https://doi.org/10.2174/1871530319666190212170140
Abdollahi E, Momtazi AA, Johnston TP, Sahebkar A (2018) Therapeutic effects of curcumin in inflammatory and immune-mediated diseases: a nature-made jack-of-all-trades? J Cell Physiol 233:830–848. https://doi.org/10.1002/jcp.25778
Abou-Raya A, Abou-Raya S (2006) Inflammation: a pivotal link between autoimmune diseases and atherosclerosis. Autoimmun Rev 5:331–337. https://doi.org/10.1016/j.autrev.2005.12.006
Aggarwal BB, Vijayalekshmi RV, Sung B (2009) Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 15:425–430. https://doi.org/10.1158/1078-0432.ccr-08-0149
Alizadeh F, Javadi M, Karami AA, Gholaminejad F, Kavianpour M, Haghighian HK (2018) Curcumin nanomicelle improves semen parameters, oxidative stress, inflammatory biomarkers, and reproductive hormones in infertile men: a randomized clinical trial. Phytother Res 32:514–521. https://doi.org/10.1002/ptr.5998
Barnes PJ (2008) The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Investig 118:3546–3556. https://doi.org/10.1172/JCI36130
Barnes PJ, Karin M (1997) Nuclear factor-κB—a pivotal transcription factor in chronic inflammatory diseases. N Engl J Med 336:1066–1071. https://doi.org/10.1056/NEJM199704103361506
Belcaro G et al (2010a) Efficacy and safety of Meriva(R), a curcumin-phosphatidylcholine complex, during extended administration in osteoarthritis patients. Altern Med Rev 15:337–344
Belcaro G et al (2010b) Product-evaluation registry of Meriva(R), a curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med 52:55–62
Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5. https://doi.org/10.1189/jlb.0306164
Blanco P, Palucka AK, Pascual V, Banchereau J (2008) Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev 19:41–52. https://doi.org/10.1016/j.cytogfr.2007.10.004
Bousquet J, Jeffery PK, Busse WW, Johnson M, Vignola AM (2000) Asthma: from bronchoconstriction to airways inflammation and remodeling. Am J Respir Crit Care Med 161:1720–1745. https://doi.org/10.1164/ajrccm.161.5.9903102
Brennan P, O’Neill LA (1998) Inhibition of nuclear factor κB by direct modification in whole cells–mechanism of action of nordihydroguaiaretic acid, curcumin and thiol modifiers. Biochem Pharmacol 55:965–973. https://doi.org/10.1016/S0006-2952(97)00535-2
Brignole F, Pisella P-J, Goldschild M, De Saint Jean M, Goguel A, Baudouin C (2000) Flow cytometric analysis of inflammatory markers in conjunctival epithelial cells of patients with dry eyes. Invest Ophthalmol Vis Sci 41:1356–1363. https://doi.org/10.1016/s0002-9394(00)00701-7
Brydges S, Kastner D (2006) The systemic autoinflammatory diseases: inborn errors of the innate immune system. Curr Top Microbiol Immunol 305:127–160
Calonge M, Enríquez-de-Salamanca A, Diebold Y, González-García MJ, Reinoso R, Herreras JM, Corell A (2010) Dry eye disease as an inflammatory disorder. Ocul Immunol Inflamm 18:244–253. https://doi.org/10.3109/09273941003721926
Camacho-Barquero L, Villegas I, Sánchez-Calvo JM, Talero E, Sánchez-Fidalgo S, Motilva V, Alarcón de la Lastra C (2007) Curcumin, a Curcuma longa constituent, acts on MAPK p38 pathway modulating COX-2 and iNOS expression in chronic experimental colitis. Int Immunopharmacol 7:333–342. https://doi.org/10.1016/j.intimp.2006.11.006
Castro CN et al (2014) Curcumin ameliorates autoimmune diabetes. Evidence in accelerated murine models of type 1 diabetes. Clin Exp Immunol 177:149–160. https://doi.org/10.1111/cei.12322
Chauhan PS, Singh D, Dash D, Singh R (2018) Intranasal curcumin regulates chronic asthma in mice by modulating NF-ĸB activation and MAPK signaling. Phytomedicine. https://doi.org/10.1016/j.phymed.2018.06.022
Chen M, Hu D-N, Pan Z, Lu C-W, Xue C-Y, Aass I (2010) Curcumin protects against hyperosmoticity-induced IL-1β elevation in human corneal epithelial cell via MAPK pathways. Exp Eye Res 90:437–443. https://doi.org/10.1016/j.exer.2009.12.004
Cho JW et al (2005) Curcumin inhibits the expression of COX-2 in UVB-irradiated human keratinocytes (HaCaT) by inhibiting activation of AP-1: p38 MAP kinase and JNK as potential upstream targets. Exp Mol Med 37:186–192. https://doi.org/10.1038/emm.2005.25
Cho JW, Lee KS, Kim CW (2007) Curcumin attenuates the expression of IL-1beta, IL-6, and TNF-alpha as well as cyclin E in TNF-alpha-treated HaCaT cells; NF-kappaB and MAPKs as potential upstream targets. Int J Mol Med 19:469–474. https://doi.org/10.3892/ijmm.19.3.469
Chong L et al (2014) Protective effect of curcumin on acute airway inflammation of allergic asthma in mice through Notch1–GATA3 signaling pathway. Inflammation 37:1476–1485. https://doi.org/10.1007/s10753-014-9873-6
Chuengsamarn S, Rattanamongkolgul S, Luechapudiporn R, Phisalaphong C, Jirawatnotai S (2012) Curcumin extract for prevention of type 2 diabetes. Diabetes Care 35:2121–2127. https://doi.org/10.2337/dc12-0116
Coskun M, Salem M, Pedersen J, Nielsen OH (2013) Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res 76:1–8. https://doi.org/10.1016/j.phrs.2013.06.007
Dinarello CA (2000) Proinflammatory cytokines. Chest 118:503–508. https://doi.org/10.1378/chest.118.2.503
Dong C, Davis RJ, Flavell RA (2002) MAP kinases in the immune response. Annu Rev Immunol 20:55–72. https://doi.org/10.1146/annurev.immunol.20.091301.131133
Dong HJ, Shang CZ, Peng DW, Xu J, Xu PX, Zhan L, Wang P (2014) Curcumin attenuates ischemia-like injury induced IL-1beta elevation in brain microvascular endothelial cells via inhibiting MAPK pathways and nuclear factor-kappaB activation. Neurol Sci 35:1387–1392. https://doi.org/10.1007/s10072-014-1718-4
Duan W, Wong WS (2006) Targeting mitogen-activated protein kinases for asthma. Curr Drug Targets 7:691–698. https://doi.org/10.2174/138945006777435353
Duran-Salgado MB, Rubio-Guerra AF (2014) Diabetic nephropathy and inflammation. World J Diabetes 5:393–398. https://doi.org/10.4239/wjd.v5.i3.393
Endo TA et al (1997) A new protein containing an SH2 domain that inhibits JAK kinases. Nature 387:921. https://doi.org/10.1038/43213
Epstein J, Docena G, MacDonald TT, Sanderson IR (2010a) Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1beta and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease. Br J Nutr 103:824–832. https://doi.org/10.1017/s0007114509992510
Epstein J, Docena G, MacDonald TT, Sanderson IR (2010b) Curcumin suppresses p38 mitogen-activated protein kinase activation, reduces IL-1β and matrix metalloproteinase-3 and enhances IL-10 in the mucosa of children and adults with inflammatory bowel disease. Br J Nutr 103:824–832. https://doi.org/10.1017/S0007114509992510
Fang TC, Yashiro-Ohtani Y, Del Bianco C, Knoblock DM, Blacklow SC, Pear WS (2007) Notch directly regulates Gata3 expression during T helper 2 cell differentiation. Immunity 27:100–110. https://doi.org/10.1016/j.immuni.2007.04.018
Firestein GS, McInnes IB (2017) Immunopathogenesis of rheumatoid arthritis. Immunity 46:183–196. https://doi.org/10.1016/j.immuni.2017.02.006
Ganjali S et al (2014) Investigation of the effects of curcumin on serum cytokines in obese individuals: a randomized controlled trial. Sci World J. https://doi.org/10.1155/2014/898361
Gao X et al (2004) Immunomodulatory activity of curcumin: suppression of lymphocyte proliferation, development of cell-mediated cytotoxicity, and cytokine production in vitro. Biochem Pharmacol 68:51–61. https://doi.org/10.1016/j.bcp.2004.03.015
Ghosh SS et al (2009) Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation. Am J Physiol Renal Physiol 296:F1146–F1157. https://doi.org/10.1152/ajprenal.90732.2008
Gonzales AM, Orlando RA (2008) Curcumin and resveratrol inhibit nuclear factor-κB-mediated cytokine expression in adipocytes. Nutr Metab 5:17. https://doi.org/10.1186/1743-7075-5-17
Gordon S (2002) Pattern recognition receptors: doubling up for the innate immune response. Cell 111:927–930. https://doi.org/10.1016/S0092-8674(02)01201-1
Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899. https://doi.org/10.1016/j.cell.2010.01.025
Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T (2005) Diabetic nephropathy: diagnosis, prevention, and treatment. Diabetes Care 28:164–176. https://doi.org/10.2337/diacare.28.1.164
Guimarães MR, Leite FRM, Spolidorio LC, Kirkwood KL, Rossa C Jr (2013) Curcumin abrogates LPS-induced pro-inflammatory cytokines in RAW 264.7 macrophages. Evidence for novel mechanisms involving SOCS-1,-3 and p38 MAPK. Arch Oral Biol 58:1309–1317. https://doi.org/10.1016/j.archoralbio.2013.07.005
Guo X-j, Zhou M, Ren L-p, Yang M, Huang S-g, Xu W-g (2009) Small interfering RNA-mediated knockdown of Notch1 in lung. Chin Med J 122:2647–2651. https://doi.org/10.3760/cma.j.issn.0366-6999.2009.21.023
Haftcheshmeh SM, Mohammadi A, Soltani A, Momtazi-Borojeni AA, Sattari M (2018) Evaluation of STAT1 and Wnt5a gene expression in gingival tissues of patients with periodontal disease. J Cell Biochem. https://doi.org/10.1002/jcb.27487
Haftcheshmeh SM, Tajbakhsh A, Kazemi M, Esmaeili SA, Mardani F, Fazeli M, Sahebkar A (2019) The clinical importance of CD4(+) CD7(–) in human diseases. J Cell Physiol 234:1179–1189. https://doi.org/10.1002/jcp.27099
Han S-S, Keum Y-S, Seo H-J, Surh Y-J (2002) Curcumin suppresses activation of NF-κB and AP-1 induced by phorbol ester in cultured human promyelocytic leukemia cells. BMB Rep 35:337–342. https://doi.org/10.5483/BMBRep.2002.35.3.337
Hanada T, Yoshimura A (2002) Regulation of cytokine signaling and inflammation. Cytokine Growth Factor Rev 13:413–421. https://doi.org/10.1016/S1359-6101(02)00026-6
Hart AL et al (2005) Characteristics of intestinal dendritic cells in inflammatory bowel diseases. Gastroenterology 129:50–65. https://doi.org/10.1053/j.gastro.2005.05.013
Holt PR, Katz S, Kirshoff R (2005) Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci 50:2191–2193. https://doi.org/10.1007/s10620-005-3032-8
Hozumi K et al (2008) Notch signaling is necessary for GATA3 function in the initiation of T cell development. Eur J Immunol 38:977–985. https://doi.org/10.1002/eji.200737688
Huber L, Distler O, Tarner I, Gay R, Gay S, Pap T (2006) Synovial fibroblasts: key players in rheumatoid arthritis. Rheumatology 45:669–675. https://doi.org/10.1093/rheumatology/kel065
Jalili-Nik M, Soltani A, Moussavi S, Ghayour-Mobarhan M, Ferns GA, Hassanian SM, Avan A (2018) Current status and future prospective of curcumin as a potential therapeutic agent in the treatment of colorectal cancer. J Cell Physiol 233:6337–6345. https://doi.org/10.1002/jcp.26368
Jin CY, Lee JD, Park C, Choi YH, Kim GY (2007) Curcumin attenuates the release of pro-inflammatory cytokines in lipopolysaccharide-stimulated BV2 microglia. Acta Pharmacol Sin 28:1645–1651. https://doi.org/10.1111/j.1745-7254.2007.00651.x
Johnson GL, Lapadat R (2002) Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases. Science 298:1911–1912. https://doi.org/10.1126/science.1072682
Jurenka JS (2009) Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev 14:141–153
Kang B, Song Y, Kim KM, Choe Y, Hwang S, Kim TS (1999a) Curcumin inhibits Th1 cytokine profile in CD4 + T cells by suppressing interleukin-12 production in macrophages. Br J Pharmacol 128:380–384. https://doi.org/10.1038/sj.bjp.0702803
Kang BY, Chung SW, Chung W-J, Im S-Y, Hwang SY, Kim TS (1999b) Inhibition of interleukin-12 production in lipopolysaccharide-activated macrophages by curcumin. Eur J Pharmacol 384:191–195
Kang BY, Song YJ, Kim KM, Choe YK, Hwang SY, Kim TS (1999c) Curcumin inhibits Th1 cytokine profile in CD4 + T cells by suppressing interleukin-12 production in macrophages. Br J Pharmacol 128:380–384. https://doi.org/10.1038/sj.bjp.0702803
Keyel PA (2014) How is inflammation initiated? Individual influences of IL-1, IL-18 and HMGB1. Cytokine 69:136–145. https://doi.org/10.1016/j.cyto.2014.03.007
Khajehdehi P, Pakfetrat M, Javidnia K, Azad F, Malekmakan L, Nasab MH, Dehghanzadeh G (2011) Oral supplementation of turmeric attenuates proteinuria, transforming growth factor-β and interleukin-8 levels in patients with overt type 2 diabetic nephropathy: a randomized, double-blind and placebo-controlled study. Scand J Urol Nephrol 45:365–370. https://doi.org/10.3109/00365599.2011.585622
Kim HY, Park EJ, E-h Joe, Jou I (2003) Curcumin suppresses Janus kinase-STAT inflammatory signaling through activation of Src homology 2 domain-containing tyrosine phosphatase 2 in brain microglia. J Immunol 171:6072–6079. https://doi.org/10.4049/jimmunol.171.11.6072
Kim G-Y et al (2005) Curcumin inhibits immunostimulatory function of dendritic cells: MAPKs and translocation of NF-κB as potential targets. J Immunol 174:8116–8124. https://doi.org/10.4049/jimmunol.174.12.8116
Kim YS et al (2007) Curcumin attenuates inflammatory responses of TNF-α-stimulated human endothelial cells. J Cardiovasc Pharmacol 50:41–49. https://doi.org/10.1097/FJC.0b013e31805559b9
Kloesch B, Becker T, Dietersdorfer E, Kiener H, Steiner G (2013) Anti-inflammatory and apoptotic effects of the polyphenol curcumin on human fibroblast-like synoviocytes. Int Immunopharmacol 15:400–405. https://doi.org/10.1016/j.intimp.2013.01.003
Kong R, Kang OH, Seo YS, Zhou T, Kim SA, Shin DW, Kwon DY (2018) MAPKs and NF-κB pathway inhibitory effect of bisdemethoxycurcumin on phorbol 12-myristate13-acetate and A23187-induced inflammation in human mast cells. Mol Med Rep 17:630–635. https://doi.org/10.3892/mmr.2017.7852
Kumar A, Dhawan S, Hardegen NJ, Aggarwal BB (1998) Curcumin (Diferuloylmethane) inhibition of tumor necrosis factor (TNF)-mediated adhesion of monocytes to endothelial cells by suppression of cell surface expression of adhesion molecules and of nuclear factor-κB activation. Biochem Pharmacol 55:775–783. https://doi.org/10.1016/S0006-2952(97)00557-1
Kunnumakkara AB, Guha S, Krishnan S, Diagaradjane P, Gelovani J, Aggarwal BB (2007) Curcumin potentiates antitumor activity of gemcitabine in an orthotopic model of pancreatic cancer through suppression of proliferation, angiogenesis, and inhibition of nuclear factor-kappaB-regulated gene products. Can Res 67:3853–3861. https://doi.org/10.1158/0008-5472.CAN-06-4257
Kyriakis JM, Avruch J (1996) Sounding the alarm: protein kinase cascades activated by stress and inflammation. J Biol Chem 271:24313–24316. https://doi.org/10.1074/jbc.271.40.24313
Landström M (2010) The TAK1–TRAF6 signalling pathway. Int J Biochem Cell Biol 42:585–589. https://doi.org/10.1016/j.biocel.2009.12.023
Lawrence T (2009) The nuclear factor NF-κB pathway in inflammation. Cold Spring Harb Perspect Biol 1:a001651. https://doi.org/10.1101/cshperspect.a001651
Lee KH et al (2012) BDMC33, a curcumin derivative suppresses inflammatory responses in macrophage-like cellular system: role of inhibition in NF-kappaB and MAPK signaling pathways. Int J Mol Sci 13:2985–3008. https://doi.org/10.3390/ijms13032985
Leonard WJ, O’Shea JJ (1998) Jaks and STATs: biological implications. Annu Rev Immunol 16:293–322. https://doi.org/10.1146/annurev.immunol.16.1.293
Li WQ, Dehnade F, Zafarullah M (2001) Oncostatin M-induced matrix metalloproteinase and tissue inhibitor of metalloproteinase-3 genes expression in chondrocytes requires Janus kinase/STAT signaling pathway. J Immunol 166:3491–3498. https://doi.org/10.4049/jimmunol.166.5.3491
Liu L et al (2013) Curcumin ameliorates dextran sulfate sodium-induced experimental colitis by blocking STAT3 signaling pathway. Int Immunopharmacol 17:314–320. https://doi.org/10.1016/j.intimp.2013.06.020
Liu JL et al (2017) Curcumin inhibits MCF-7 cells by modulating the NF-kappaB signaling pathway. Oncol Lett 14:5581–5584. https://doi.org/10.3892/ol.2017.6860
MacDonald TT, Monteleone I, Fantini MC, Monteleone G (2011) Regulation of homeostasis and inflammation in the intestine. Gastroenterology 140:1768–1775. https://doi.org/10.1053/j.gastro.2011.02.047
Martinon F, Tschopp J (2004) Inflammatory caspases: linking an intracellular innate immune system to autoinflammatory diseases. Cell 117:561–574. https://doi.org/10.1016/j.cell.2004.05.004
Medzhitov R (2008) Origin and physiological roles of inflammation. Nature 454:428. https://doi.org/10.1038/nature07201
Medzhitov R (2010) Inflammation 2010: new adventures of an old flame. Cell 140:771–776. https://doi.org/10.1016/j.cell.2010.03.006
Meinecke I, Rutkauskaite E, Gay S, Pap T (2005) The role of synovial fibroblasts in mediating joint destruction in rheumatoid arthritis. Curr Pharm Des 11:563–568. https://doi.org/10.2174/1381612053381945
Mohammadi A et al (2017) Modulatory effects of curcumin on apoptosis and cytotoxicity-related molecules in HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) patients. Biomed Pharmacother 85:457–462. https://doi.org/10.1016/j.biopha.2016.11.050
Mohammadi A, Blesso CN, Barreto GE, Banach M, Majeed M, Sahebkar A (2018a) Macrophage plasticity, polarization and function in response to curcumin, a diet-derived polyphenol, as an immunomodulatory agent. J Nutr Biochem 66:1–16. https://doi.org/10.1016/j.jnutbio.2018.12.005
Mohammadi A, Sharifi A, Pourpaknia R, Mohammadian S, Sahebkar A (2018b) Manipulating macrophage polarization and function using classical HDAC inhibitors: implications for autoimmunity and inflammation. Crit Rev Oncol Hematol 128:1–18. https://doi.org/10.1016/j.critrevonc.2018.05.009
Momtazi AA, Sahebkar A (2016) Difluorinated curcumin: a promising curcumin analogue with improved anti-tumor activity and pharmacokinetic profile. Curr Pharm Des 22:4386–4397. https://doi.org/10.2174/1381612822666160527113501
Momtazi AA, Shahabipour F, Khatibi S, Johnston TP, Pirro M, Sahebkar A (2016) Curcumin as a MicroRNA regulator in cancer: a review. Rev Physiol Biochem Pharmacol 171:1–38. https://doi.org/10.1007/112_2016_3
Momtazi-Borojeni AA, Haftcheshmeh SM, Esmaeili S-A, Johnston TP, Abdollahi E, Sahebkar A (2017) Curcumin: a natural modulator of immune cells in systemic lupus erythematosus. Autoimmun Rev. https://doi.org/10.1016/j.autrev.2017.11.016
Moreillon JJ et al (2013) The use of an anti-inflammatory supplement in patients with chronic kidney disease. J Complement Integr Med. https://doi.org/10.1515/jcim-2012-0011
Moreno JA et al (2018) Targeting inflammation in diabetic nephropathy: a tale of hope. Expert Opin Investig Drugs 27:917–930. https://doi.org/10.1080/13543784.2018.1538352
Natarajan C, Bright JJ (2002) Curcumin inhibits experimental allergic encephalomyelitis by blocking IL-12 signaling through Janus kinase-STAT pathway in T lymphocytes. J Immunol 168:6506–6513. https://doi.org/10.4049/jimmunol.168.12.6506
Osborne BA, Minter LM (2007) Notch signalling during peripheral T-cell activation and differentiation. Nat Rev Immunol 7:64. https://doi.org/10.1038/nri1998
O’shea JJ, Plenge R (2012) JAK and STAT signaling molecules in immunoregulation and immune-mediated disease. Immunity 36:542–550. https://doi.org/10.1016/j.immuni.2012.03.014
O’shea JJ, Holland SM, Staudt LM (2013) JAKs and STATs in immunity, immunodeficiency, and cancer. N Engl J Med 368:161–170. https://doi.org/10.1056/NEJMra1202117
O’Shea JJ, Schwartz DM, Villarino AV, Gadina M, McInnes IB, Laurence A (2015) The JAK-STAT pathway: impact on human disease and therapeutic intervention. Ann Rev Med 66:311–328. https://doi.org/10.1146/annurev-med-051113-024537
Palm NW, Medzhitov R (2009) Pattern recognition receptors and control of adaptive immunity. Immunol Rev 227:221–233. https://doi.org/10.1111/j.1600-065X.2008.00731.x
Pan Y et al (2013) Targeting JNK by a new curcumin analog to inhibit NF-kB-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice. PLoS One 8:e79084. https://doi.org/10.1371/journal.pone.0079084
Panahi Y, Sahebkar A, Parvin S, Saadat A (2012) A randomized controlled trial on the anti-inflammatory effects of curcumin in patients with chronic sulphur mustard-induced cutaneous complications. Ann Clin Biochem 49:580–588. https://doi.org/10.1258/acb.2012.012040
Panahi Y, Saadat A, Beiraghdar F, Sahebkar A (2014) Adjuvant therapy with bioavailability-boosted curcuminoids suppresses systemic inflammation and improves quality of life in patients with solid tumors: a randomized double-blind placebo-controlled trial. Phytother Res 28:1461–1467. https://doi.org/10.1002/ptr.5149
Panahi Y, Ghanei M, Bashiri S, Hajihashemi A, Sahebkar A (2015) Short-term curcuminoid supplementation for chronic pulmonary complications due to sulfur mustard intoxication: positive results of a randomized double-blind placebo-controlled trial. Drug Res 65:567–573. https://doi.org/10.1055/s-0034-1389986
Panahi Y, Hosseini MS, Khalili N, Naimi E, Simental-Mendía LE, Majeed M, Sahebkar A (2016a) Effects of curcumin on serum cytokine concentrations in subjects with metabolic syndrome: a post hoc analysis of a randomized controlled trial. Biomed Pharm 82:578–582. https://doi.org/10.1016/j.biopha.2016.05.037
Panahi Y, Kianpour P, Mohtashami R, Jafari R, Simental-Mendiá LE, Sahebkar A (2016b) Curcumin lowers serum lipids and uric acid in subjects with nonalcoholic fatty liver disease: a randomized controlled trial. J Cardiovasc Pharmacol 68:223–229. https://doi.org/10.1097/FJC.0000000000000406
Panahi Y, Khalili N, Sahebi E, Namazi S, Karimian MS, Majeed M, Sahebkar A (2017a) Antioxidant effects of curcuminoids in patients with type 2 diabetes mellitus: a randomized controlled trial. Inflammopharmacology 25:25–31. https://doi.org/10.1007/s10787-016-0301-4
Panahi Y, Kianpour P, Mohtashami R, Jafari R, Simental-Mendía LE, Sahebkar A (2017b) Efficacy and safety of phytosomal curcumin in non-alcoholic fatty liver disease: a randomized controlled trial. Drug Res 67:244–251. https://doi.org/10.1055/s-0043-100019
Park C-S (2010) Eosinophilic bronchitis, eosinophilia associated genetic variants, and notch signaling in asthma. Allergy Asthma Immunol Res 2:188–194. https://doi.org/10.4168/aair.2010.2.3.188
Rahimnia A-R, Panahi Y, Alishiri G, Sharafi M, Sahebkar A (2015) Impact of supplementation with curcuminoids on systemic inflammation in patients with knee osteoarthritis: findings from a randomized double-blind placebo-controlled trial. Drug Res 65:521–525. https://doi.org/10.1055/s-0034-1384536
Sahebkar A (2013) Why it is necessary to translate curcumin into clinical practice for the prevention and treatment of metabolic syndrome? Biofactors 39:197–208. https://doi.org/10.1002/biof.1062
Sahebkar A, Cicero AFG, Simental-Mendía LE, Aggarwal BB, Gupta SC (2016) Curcumin downregulates human tumor necrosis factor-α levels: a systematic review and meta-analysis of randomized controlled trials. Pharmacol Res 107:234–242. https://doi.org/10.1016/j.phrs.2016.03.026
Samadian F et al (2017) Evaluation of curcumin’s effect on inflammation in hemodialysis patients. Clin Nutr ESPEN 22:19–23. https://doi.org/10.1016/j.clnesp.2017.09.006
Schindler C, Levy DE, Decker T (2007) JAK-STAT signaling: from interferons to cytokines. J Biol Chem 282:20059–20063. https://doi.org/10.1074/jbc.R700016200
Seger R, Krebs EG (1995) The MAPK signaling cascade. FASEB J 9:726–735
Sen R, Baltimore D (1986) Inducibility of κ immunoglobulin enhancer-binding protein NF-κB by a posttranslational mechanism. Cell 47:921–928. https://doi.org/10.1016/0092-8674(86)90807-X
Sha WC, Liou H-C, Tuomanen EI, Baltimore D (1995) Targeted disruption of the p50 subunit of NF-κB leads to multifocal defects in immune responses. Cell 80:321–330. https://doi.org/10.1016/0092-8674(95)90415-8
Shakibaei M, John T, Schulze-Tanzil G, Lehmann I, Mobasheri A (2007) Suppression of NF-kappaB activation by curcumin leads to inhibition of expression of cyclo-oxygenase-2 and matrix metalloproteinase-9 in human articular chondrocytes: implications for the treatment of osteoarthritis. Biochem Pharmacol 73:1434–1445. https://doi.org/10.1016/j.bcp.2007.01.005
Shelmadine BD et al (2017) A pilot study to examine the effects of an anti-inflammatory supplement on eicosanoid derivatives in patients with chronic kidney disease. J Altern Complement Med 23:632–638. https://doi.org/10.1089/acm.2016.0007(New York, NY)
Soetikno V et al (2011) Curcumin ameliorates macrophage infiltration by inhibiting NF-κB activation and proinflammatory cytokines in streptozotocin induced-diabetic nephropathy. Nutr Metab 8:35. https://doi.org/10.1186/1743-7075-8-35
Soltani A, Salmaninejad A, Jalili-Nik M, Soleimani A, Javid H, Hashemy SI, Sahebkar A (2019) 5′-Adenosine monophosphate-activated protein kinase: a potential target for disease prevention by curcumin. J Cell Physiol 234:2241–2251. https://doi.org/10.1002/jcp.27192
Soveyd N, Abdolahi M, Djalali M, Hatami M, Tafakhori A, Sarraf P, Honarvar NM (2018) The combined effects of omega -3 fatty acids and nano-curcumin supplementation on intercellular adhesion molecule-1 (ICAM-1) gene expression and serum levels in migraine patients. CNS Neurol Disord Drug Targets 16:1120–1126. https://doi.org/10.2174/1871527317666171213154749
Stanimirovic D, Satoh K (2000) Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 10:113–126. https://doi.org/10.1111/j.1750-3639.2000.tb00248.x
Starr R et al (1997) A family of cytokine-inducible inhibitors of signalling. Nature 387:917. https://doi.org/10.1038/43206
Stat CJK, Egf P (2005) The Jak-STAT pathway in rheumatoid arthritis. J Rheumatol 32:1650–1653
Stevenson W, Chauhan SK, Dana R (2012) Dry eye disease: an immune-mediated ocular surface disorder. Arch Ophthalmol 130:90–100. https://doi.org/10.1001/archophthalmol.2011.364(Chicago, Ill : 1960)
Suresh S, Sankar P, Telang AG, Kesavan M, Sarkar SN (2018) Nanocurcumin ameliorates Staphylococcus aureus-induced mastitis in mouse by suppressing NF-κB signaling and inflammation. Int Immunopharmacol 65:408–412. https://doi.org/10.1016/j.intimp.2018.10.034
Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140:805–820. https://doi.org/10.1016/j.cell.2010.01.022
Tamiya T, Kashiwagi I, Takahashi R, Yasukawa H, Yoshimura A (2011) Suppressors of cytokine signaling (SOCS) proteins and JAK/STAT pathways: regulation of T-cell inflammation by SOCS1 and SOCS3. Arterioscler Thromb Vasc Biol 31:980–985. https://doi.org/10.1161/ATVBAHA.110.207464
Teymouri M, Pirro M, Johnston TP, Sahebkar A (2017) Curcumin as a multifaceted compound against human papilloma virus infection and cervical cancers: a review of chemistry, cellular, molecular, and preclinical features. Biofactors 43:331–346. https://doi.org/10.1002/biof.1344
Usharani P, Mateen AA, Naidu MU, Raju YS, Chandra N (2008) Effect of NCB-02, atorvastatin and placebo on endothelial function, oxidative stress and inflammatory markers in patients with type 2 diabetes mellitus: a randomized, parallel-group, placebo-controlled, 8-week study. Drugs R&D 9:243–250. https://doi.org/10.2165/00126839-200809040-00004
Wei L, Laurence A, Elias KM, O’Shea JJ (2007) IL-21 is produced by Th17 cells and drives IL-17 production in a STAT3-dependent manner. J Biol Chem 282:34605–34610. https://doi.org/10.1074/jbc.M705100200
Xiao C, Ghosh S (2005) NF-kappaB, an evolutionarily conserved mediator of immune and inflammatory responses. Adv Exp Med Biol 560:41–45. https://doi.org/10.1007/0-387-24180-9_5
Xie L, Li X-K, Funeshima-Fuji N, Kimura H, Matsumoto Y, Isaka Y, Takahara S (2009) Amelioration of experimental autoimmune encephalomyelitis by curcumin treatment through inhibition of IL-17 production. Int Immunopharmacol 9:575–581. https://doi.org/10.1016/j.intimp.2009.01.025
Xu Y, Liu L (2017) Curcumin alleviates macrophage activation and lung inflammation induced by influenza virus infection through inhibiting the NF-kappaB signaling pathway. Influenza Other Respir Viruses 11:457–463. https://doi.org/10.1111/irv.12459
Yang X et al (2017) Curcumin reduces lung inflammation via Wnt/β-catenin signaling in mouse model of asthma. J Asthma 54:335–340. https://doi.org/10.1080/02770903.2016.1218018
Yekollu SK, Thomas R, O’Sullivan B (2011) Targeting curcusomes to inflammatory dendritic cells inhibits NF-kappaB and improves insulin resistance in obese mice. Diabetes 60:2928–2938. https://doi.org/10.2337/db11-0275
Zhang C, Li B, Zhang X, Hazarika P, Aggarwal BB, Duvic M (2010a) Curcumin selectively induces apoptosis in cutaneous T-cell lymphoma cell lines and patients’ PBMCs: potential role for STAT-3 and NF-kappaB signaling. Journal Investig Dermatol 130:2110–2119. https://doi.org/10.1038/jid.2010.86
Zhang L et al (2010b) Demethoxycurcumin, a natural derivative of curcumin attenuates LPS-induced pro-inflammatory responses through down-regulation of intracellular ROS-related MAPK/NF-κB signaling pathways in N9 microglia induced by lipopolysaccharide. Int Immunopharmacol 10:331–338. https://doi.org/10.1016/j.intimp.2009.12.004
Zhang X, Wu J, Ye B, Wang Q, Xie X, Shen H (2016) Protective effect of curcumin on TNBS-induced intestinal inflammation is mediated through the JAK/STAT pathway. BMC Complement Altern Med 16:299. https://doi.org/10.1186/s12906-016-1273-z
Zhang N et al (2017) Effect of curcumin on acute spinal cord injury in mice via inhibition of inflammation and TAK1 pathway. Pharmacol Rep 69:1001–1006. https://doi.org/10.1016/j.pharep.2017.02.012
Zhao H-M et al (2016) Curcumin suppressed activation of dendritic cells via JAK/STAT/SOCS signal in mice with experimental colitis. Front Pharmacol 7:455. https://doi.org/10.3389/fphar.2016.00455
Zhou L et al (2007) IL-6 programs T H-17 cell differentiation by promoting sequential engagement of the IL-21 and IL-23 pathways. Nat Immunol 8:967. https://doi.org/10.1038/ni1488
Zhu J, Yamane H, Paul WE (2010) Differentiation of effector CD4 T cell populations. Annu Rev Immunol 28:445–489. https://doi.org/10.1146/annurev-immunol-030409-101212
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Kahkhaie, K.R., Mirhosseini, A., Aliabadi, A. et al. Curcumin: a modulator of inflammatory signaling pathways in the immune system. Inflammopharmacol 27, 885–900 (2019). https://doi.org/10.1007/s10787-019-00607-3
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DOI: https://doi.org/10.1007/s10787-019-00607-3
Keywords
- Curcumin
- Inflammation
- Inflammatory signaling pathway
- Inflammatory diseases