Skip to main content

Advertisement

SpringerLink
Log in

Cholecystokinin octapeptide exerts its therapeutic effects on collagen-induced arthritis by suppressing both inflammatory and Th17 responses

  • Original Article
  • Published:
Rheumatology International Aims and scope Submit manuscript

Abstract

The purpose of this study was to evaluate the potential therapeutic effect of cholecystokinin octapeptide (CCK-8) on collagen-induced arthritis (CIA), an accepted murine experimental disease model with diverse histopathological features similar to human rheumatoid arthritis (RA). CIA was induced in DBA/1J mice by immunization with chicken collagen type II (CII). CCK-8 at different doses was intraperitoneally administered daily for 1 week. Mice treated with CCK-8 at doses of 5 and 10 nmol but not 1 nmol displayed much delayed onset of CIA and significantly lower incidence and decreased severity of arthritis. CCK-8 treatment significantly reduced the production of cytokines (IL-17, IL-23, IL-6 and TNF-α) and chemokines monocyte chemoattractant protein 1 in the joints of arthritic mice or in synovial cell culture supernatant, and increased the levels of IFN-γ and TGF-β. T cells from CCK-8 treated mice proliferated much less, produced low level of IL-17 and high levels of IFN-γ and TGF-β. Moreover, CCK-8 treated mice showed lower levels of CII-specific IgG, particularly that of IgG2a, in sera than those from control mice. These results indicate that CCK-8 is effective in suppressing both inflammatory and Th17 responses in CIA. CCK-8 may represent a new therapeutic modality for rheumatoid arthritis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. VanderBorght A, Geusens P, Raus J, Stinissen P (2001) The autoimmune pathogenesis of rheumatoid arthritis: role of autoreactive T cells and immunotherapies. Semin Arthritis Rheum 31:160–175. doi:10.1053/sarh.2001.27736

    Article  PubMed  CAS  Google Scholar 

  2. Zhao JX, Li R, Shi JX, Long L, Li ZG (2008) Mucosal administration of an altered CII263-272 peptide inhibits collagen-induced arthritis by suppression of Th1/Th17 cells and expansion of regulatory T cells. Rheumatol Int 29:9–16. doi:10.1007/s00296-008-0634-4

    Article  PubMed  Google Scholar 

  3. Elena GR, Alejo C, Francisco O, Mario D (2007) Adrenomedullin protects from experimental arthritis by down-regulating inflammation and Th1 response and inducing regulatory T cells. Am J Pathol 170:263–271. doi:10.2353/ajpath.2007.060596

    Article  Google Scholar 

  4. Mario D, Catalina A, Carmen M, Javier L, Rosa PG (2001) Vasoactive intestinal peptide prevents experimental arthritis by downregulating both autoimmune and inflammatory components of the disease. Nat Med 7:563–568. doi:10.1038/87887

    Article  Google Scholar 

  5. Janette FC, María Inés VR, Antonio RC (2007) Autoimmune inflammation from the Th17 perspective. Autoimmun Rev 6:169–175. doi:10.1016/j.autrev.2006.10.002

    Article  Google Scholar 

  6. Harrington LE, Mangan PR, Weaver CT (2006) Expanding the effector CD4 T-cell repertoire: the Th17 lineage. Curr Opin Immunol 18:349–356. doi:10.1016/j.coi.2006.03.017

    Article  PubMed  CAS  Google Scholar 

  7. Langrish CL, Chen Y, Blumenschein WM et al (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240. doi:10.1084/jem.20041257

    Article  PubMed  CAS  Google Scholar 

  8. Lubberts E, Koenders MI, van der Berg W (2005) The role of T cell interleukin-17 in conducting destructive arthritis: lessons from animal models. Arthritis Res Ther 7:29–37. doi:10.1186/ar1478

    Article  PubMed  CAS  Google Scholar 

  9. Brand DD, Kang AH, Rosloniec EF (2003) Immunopathogenesis of collagen arthritis. Springer Semin Immunopathol 25:3–18. doi:10.1007/s00281-003-0127-1

    Article  PubMed  Google Scholar 

  10. Elena GR, Alejo C, Nieves V, O’V Francisco, Mario D (2007) Therapeutic effect of urocortin on collagen-induced arthritis by down-regulation of inflammatory and Th1 responses and induction of regulatory T cells. Arthritis Rheum 56:531–543. doi:10.1002/art.22394

    Article  Google Scholar 

  11. Ni ZY, Cong B, Li SJ, Ma CL, Yan YX, Xu JR, Zhang GZ (2007) Effects of cholecystokinin octapeptide on expression of IL-1β, IL-6, IL-4 and IL-10 in lipopolysaccharide-attacked mice. Chin J Pathophysiol 23:331–335

    CAS  Google Scholar 

  12. Song N, Li SJ, Cong B et al (2009) Cholecystokinin octapeptide modulates Th1/Th2 imbalance in splenocytes of KLH-immunized mice. Chin J Pathophysiol 25:313–317

    CAS  Google Scholar 

  13. Jin YH, Zhao ZS, Cong B, Xu JR, Yao YX, Li SJ, Ling YL (2005) Effect of cholecystokinin octapeptide-8 on the production of matrix metalloproteinases of rat fibroblast-like synovial cell line RSC-364. Chin J Rheumatol 9:193–196

    Google Scholar 

  14. Manni L, Lundeberg T, Tirassa P, Aloe L (2002) Role of cholecystokinin-8 in nerve growth factor and nerve growth factor mRNA expression in carrageenan-induced joint inflammation in adult rats. Rheumatology 41:787–792

    Article  PubMed  CAS  Google Scholar 

  15. Elena GR, Amelia FM, Alejo C, Mario D (2006) Vasoactive intestinal peptide induces CD4+, CD25+ T regulatory cells with therapeutic effect in collagen-induced arthritis. Arthritis Rheum 54:864–876. doi:10.1002/art.21652

    Article  Google Scholar 

  16. Kim KS, Choi YH, Kim KH et al (2004) Protective and anti-arthritic effects of deer antler aqua-acupuncture (DAA), inhibiting dihydroorotate dehydrogenase, on phosphate ions mediated chondrocyte apoptosis and rat collagen-induced arthritis. Int Immunopharmacol 4:963–973. doi:10.1016/j.intimp.2004.04.010

    Article  PubMed  CAS  Google Scholar 

  17. Nishikawa M, Myoui A, Tomita T, Takahi K, Nampei A, Yoshikawa H (2003) Prevention of the onset and progression of collagen induced arthritis in rats by the potent p38 mitogen-activated protein kinase inhibitor FR167653. Arthritis Rheum 48:2670–2681. doi:10.1002/art.11227

    Article  PubMed  CAS  Google Scholar 

  18. Butler DM, Malfait AM, Mason LJ et al (1997) DBA/1 mice expressing the human TNFα transgene develop a severe, erosive arthritis: characterization of the cytokine cascade and cellular composition. J Immunol 159:2867–2876

    PubMed  CAS  Google Scholar 

  19. Hirayasu K, Kazuko S, Wang YN et al (2006) Critical role of M. tuberculosis for dendritic cell maturation to induce collagen-induced arthritis in H-2b background of C57BL/6 mice. Immunology 118:233–239. doi:10.1111/j.1365-2567.2006.02361.x

    Article  Google Scholar 

  20. Seetharaman R, Mora AL, Nabozny G, Boothby M, Chen J (1999) Essential role of T-cell NF-kappa B activation in collagen-induced arthritis. J Immunol 163:1577–1583

    PubMed  CAS  Google Scholar 

  21. Fionula MB, Iain BM (2008) Evidence that cytokines play a role in rheumatoid arthritis. J Clin Invest 118:3537–3545. doi:10.1172/JCI36389

    Article  Google Scholar 

  22. Anthony DD, Haqqi TM (1999) Collagen-induced arthritis in mice: an animal model to study the pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol 17:240–244

    PubMed  CAS  Google Scholar 

  23. O’Garra A (1998) Cytokines induce the development of functionally heterogeneous T helper cell subsets. Immunity 8:275–283. doi:10.1016/S1074-7613(00)80533-6

    Article  PubMed  Google Scholar 

  24. Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM (2006) Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24:677–688. doi:10.1016/j.immuni.2006.06.002

    Article  PubMed  CAS  Google Scholar 

  25. Corte’s M, Canellada A, Miranda S, Dokmetjian J, Gentile T (2008) Placental secreted factors: their role in the regulation of anti-CII antibodies and amelioration of collagen induced arthritis in rats. Immunol Lett 119:42–48. doi:10.1016/j.imlet.2008.04.001

    Article  Google Scholar 

  26. Feldmann M, Brennan FM, Maini RN (1996) Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 14:397–440. doi:10.1146/annurev.immunol.14.1.397

    Article  PubMed  CAS  Google Scholar 

  27. Koch AE (2005) Chemokines and their receptors in rheumatoid arthritis: future targets? Arthritis Rheum 52:710–721. doi:10.1002/art.20932

    Article  PubMed  Google Scholar 

  28. Kuruvilla AP, Shah R, Hochwald GM, Liggitt HD, Palladito MA, Thorbecke GJ (1991) Protective effect of transforming growth factor β1 on experimental autoimmune diseases in mice. Proc Natl Acad Sci USA 88:2918–2921

    Article  PubMed  CAS  Google Scholar 

  29. Cooper SM, Sriram S, Ranges GE (1988) Suppression of murine collagen-induced arthritis with monoclonal anti-Ia antibodies and augmentation with IFN-gamma. J Immunol 141:1958–1962

    PubMed  CAS  Google Scholar 

  30. Boissier MC, Chiocchia G, Bessis N, Hajnal J, Garotta G, Nicoletti F, Fournier C (1995) Biphasic effect of interferon-γ in murine collagen-induced arthritis. Eur J Immunol 25:1184–1190. doi:10.1002/eji.1830250508

    Article  PubMed  CAS  Google Scholar 

  31. Williams RO, Williams DG, Feldmann M, Maini RN (1993) Increased limb involvement in murine collagen-induced arthritis following treatment with anti-interferon-gamma. Clin Exp Immunol 92:323–327. doi:10.1111/j.1365-2249.1993.tb03399.x

    Article  PubMed  CAS  Google Scholar 

  32. Nakajima H, Hiyama Y, Takamori H, Tsukada W (1993) Cell-mediated transfer of collagen-induced arthritis in mice and its application to the analysis of the inhibitory effects of interferon-gamma and cyclophosphamide. Clin Exp Immunol 92:328–335. doi:10.1111/j.1365-2249.1993.tb03400.x

    Article  PubMed  CAS  Google Scholar 

  33. Vermeire K, Heremans H, Vandeputte M, Huang S, Billiau A, Maththys P (1997) Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J Immunol 158:5507–5513

    PubMed  CAS  Google Scholar 

  34. Manoury-Schwartz B, Chiocchia G, Bessis N et al (1997) High susceptibility to collagen-induced arthritis in mice lacking IFN-gamma receptors. J Immunol 158:5501–5506

    PubMed  CAS  Google Scholar 

  35. Li S, Ni Z, Cong B, Gao W, Xu S, Wang C, Yao Y, Ma C, Ling Y (2007) CCK-8 inhibits LPS-induced IL-1 beta production in pulmonary interstitial macrophages by modulating PKA, p38, and NF-kappaB pathway. Shock 27:678–686. doi:10.1097/shk.0b013e3180ze26dd

    Article  PubMed  CAS  Google Scholar 

  36. Sheibanie AF, Khayrullina T, Safadi FF, Ganea D (2007) Prostaglandin E2 exacerbates collagen-induced arthritis in mice through the inflammatory interleukin-23/interleukin-17 axis. Arthritis Rheum 56:2608–2619. doi:10.1002/art.22794

    Article  PubMed  CAS  Google Scholar 

  37. Dong C (2006) Diversification of T-helper-cell lineages: finding the family root of IL-17-producing cells. Nat Rev Immunol 6:329–333. doi:10.1038/nri1807

    Article  PubMed  CAS  Google Scholar 

  38. Tato CM, O’Shea JJ (2006) Immunology: what does it mean to be just 17? Nature 441:166–168. doi:10.1038/441166a

    Article  PubMed  CAS  Google Scholar 

  39. Han DY, Cong B, Li SJ et al (2008) Effect of CCK-8 on IL-12 secreted in murine bone marrow-derived dendritic cell induced by LPS. Chin Pharmacol Bull 24:357–361

    CAS  Google Scholar 

  40. Wraith DC, Nicolson KS, Whitlet NT (2004) Regulatory CD4+ T cells and the control of autoimmune disease. Curr Opin Immunol 16:695–701. doi:10.1016/j.coi.2004.09.015

    Article  PubMed  CAS  Google Scholar 

  41. Morgan ME, Flierman R, van Duivenvoorde LM et al (2005) Effective treatment of collagen-induced arthritis by adoptive transfer of CD25+ regulatory T cells. Arthritis Rheum 52:2212–2221. doi:10.1002/art21195

    Article  PubMed  CAS  Google Scholar 

  42. Mukherjee P, Wu B, Mayton L, Kim SH, Robbins PD, Wooley PH (2003) TNF receptor gene therapy results in suppression of IgG2a anticollagen antibody in collagen induced arthritis. Ann Rheum Dis 62:707–714. doi:10.1136/ard.62.8.707

    Article  PubMed  CAS  Google Scholar 

  43. Susumu N, Aya N, Katsuko S, Yoichiro I (2003) Suppression of immune induction of collagen-induced arthritis in IL-17-deficient mice. J Immunol 171:6173–6177

    Google Scholar 

Download references

Acknowledgments

This work was supported by grants from National Natural Science Foundation of China (No. 30770839); Natural Science Foundation of Hebei Province (No. C2007000833); China Postdoctoral Science Foundation funded project (No. 20080440822).

Conflict of interest statement

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Institute of Basic Medicine, Hebei Medical University, Zhongshan East Road 361, Shijiazhuang, 050017, Hebei, People’s Republic of China

    Qiaoxia Li, Bin Cong, Jingge Zhang, Haiying Chen, Chunling Ma, Jin Qin, Di Wen & Feng Yu

  2. Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, People’s Republic of China

    Qiaoxia Li, Baoen Shan & Tao Wang

Authors
  1. Qiaoxia Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bin Cong
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Baoen Shan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jingge Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Haiying Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Chunling Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Jin Qin
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Di Wen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Feng Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bin Cong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Li, Q., Cong, B., Shan, B. et al. Cholecystokinin octapeptide exerts its therapeutic effects on collagen-induced arthritis by suppressing both inflammatory and Th17 responses. Rheumatol Int 31, 1291–1298 (2011). https://doi.org/10.1007/s00296-010-1476-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00296-010-1476-4

Keywords

Search

Navigation