Rheumatology International

, Volume 35, Issue 1, pp 35–41 | Cite as

Could retinoids be a potential treatment for rheumatic diseases?

Review Article
First Online:
Received:
Accepted:

Abstract

Retinoid, a derivative of vitamin A, is a general term used to describe compounds that bind to and activate retinoic acid receptors [RARs (RARα, RARβ, and RARγ)] and/or retinoid X receptors [RXRs (RXRα, RXRβ, and RXRγ)]. They have been shown to surpress the differentiation of Th1/Th17 cells and induce the development of Th1/regulatory T cells. They also affect the proliferation of B cells as both an inducer and suppressor. Furthermore, retinoids may induce the maturation of dendritic cells and production of interleukin-10 from monocytes/macrophages. We recently demonstrated that retinoids suppressed the production of reactive oxygen species, the release of elastase from neutrophils by inhibiting mitogen-activated protein kinase signals, and both the migration speed and chemotaxis directionality of neutrophils. Retinoids, such as all-trans retinoic acid and tamibarotene, were previously shown to have positive effects on animal models of several rheumatic diseases, including arthritis, myositis, and vasculitis in vivo. Moreover, retinoids have been used in a pilot study to effectively treat patients with lupus nephritis and systemic sclerosis. We herein reviewed the effects of retinoids on immune cells, animal models of rheumatic diseases, and rheumatic patients.

Keywords

Retinoid T cells B cells Rheumatoid arthritis Rheumatic diseases 
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Notes

Conflict of interest

Dr. Nanki reports grants and personal fees from Chugai Pharmaceutical Co., LTD., grants and personal fees from Eisai Co., LTD., grants from Ono Pharmaceutical Co., LTD., grants and personal fees from Mitsubishi Tanabe Pharma Corporation., grants and personal fees from Takeda Pharmaceutical Co., LTD, grants and personal fees from AbbVie Inc., personal fees from UCB Japan Co. Ltd., personal fees from Astellas Pharma Inc., grants from Pfizer Japan Inc., personal fees from Bristol-Myers Squibb, personal fees from Santen Pharmaceutical Co., Ltd., personal fees from Taisho Toyama Pharmaceutical Co., Ltd., and grants from Asahi Kasei Pharma Corporation outside the submitted work.

References

  1. 1.
    Tanaka Y (2012) Intensive treatment and treatment holiday of TNF-inhibitors in rheumatoid arthritis. Curr Opin Rheumatol 24:319–326PubMedCrossRefGoogle Scholar
  2. 2.
    Takeuchi T, Miyasaka N, Inoue K, Abe T, Koike T, RISING study (2009) Impact of trough serum level on radiographic and clinical response to infliximab plus methotrexate in patients with rheumatoid arthritis: results from the RISING study. Mod Rheumatol 19:478–487PubMedCentralPubMedCrossRefGoogle Scholar
  3. 3.
    Harigai M, Koike R, Miyasaka N, PPuA-TNFTPS Group (2007) Pneumocystis pneumonia associated with infliximab in Japan. N Engl J Med 357:1874–1876PubMedCrossRefGoogle Scholar
  4. 4.
    Komano Y, Tanaka M, Nanki T, Koike R, Sakai R, Kameda H et al (2011) Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety. J Rheumatol 38:1258–1264PubMedCrossRefGoogle Scholar
  5. 5.
    Tombetti E, Franchini S, Papa M, Sabbadini MG, Baldissera E (2013) Treatment of refractory Takayasu arteritis with tocilizumab: 7 Italian patients from a single referral center. J Rheumatol 40:2047–2051PubMedCrossRefGoogle Scholar
  6. 6.
    Rouster-Stevens KA, Ferguson L, Morgan G, Huang CC, Pachman LM (2014) Pilot study of etanercept in patients with refractory juvenile dermatomyositis. Arthritis Care Res (Hoboken) 66:783–787Google Scholar
  7. 7.
    Bird HA, Hill J, Sitton NG, Dixon JS, Wright V (1988) A clinical and biochemical evaluation of etretinate in rheumatoid arthritis. Rheumatol Int 8:55–59PubMedCrossRefGoogle Scholar
  8. 8.
    Gravallese EM, Handel ML, Coblyn J, Anderson RJ, Sperling RI, Karlson EW et al (1996) N-[4-hydroxyphenyl] retinamide in rheumatoid arthritis: a pilot study. Arthritis Rheum 39:1021–1026PubMedCrossRefGoogle Scholar
  9. 9.
    Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M et al (2007) Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science 317:256–260PubMedCrossRefGoogle Scholar
  10. 10.
    Sato A, Watanabe K, Kaneko K, Murakami Y, Ishido M, Miyasaka N et al (2010) The effect of synthetic retinoid, Am 80, on T helper cell development and antibody production in murine collagen-induced arthritis. Mod Rheumatol 20:244–251PubMedCrossRefGoogle Scholar
  11. 11.
    Ohyanagi N, Ishido M, Suzuki F, Kaneko K, Kubota T, Miyasaka N et al (2009) Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivo. Arthritis Rheum 60:3118–3127PubMedCrossRefGoogle Scholar
  12. 12.
    Miyabe C, Miyabe Y, Miura NN, Takahashi K, Terashima Y, Toda E et al (2013) Am 80, a retinoic acid receptor agonist, ameliorates murine vasculitis through the suppression of neutrophil migration and activation. Arthritis Rheum 65:503–512PubMedCrossRefGoogle Scholar
  13. 13.
    Chambon P (1996) A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954PubMedGoogle Scholar
  14. 14.
    Blomhoff R, Blomhoff HK (2006) Overview of retinoid metabolism and function. J Neurobiol 66:606–630PubMedCrossRefGoogle Scholar
  15. 15.
    Mora JR, Iwata M, von Andrian UH (2008) Vitamin effects on the immune system: vitamins A and D take centre stage. Nat Rev Immunol 8(9):685–698PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    van de Kerkhof PC (2006) Update on retinoid therapy of psoriasis in: an update on the use of retinoids in dermatology. Dermatol Ther 19(5):252–263PubMedCrossRefGoogle Scholar
  17. 17.
    Smith EV, Grindlay DJ, Williams HC (2011) What’s new in acne? An analysis of systematic reviews published in 2009–2010. Clin Exp Dermatol 36:119–122 quiz 23PubMedCrossRefGoogle Scholar
  18. 18.
    Kagechika H (2002) Novel synthetic retinoids and separation of the pleiotropic retinoidal activities. Curr Med Chem 9:591–608PubMedCrossRefGoogle Scholar
  19. 19.
    Ohnishi K (2007) PML-RARalpha inhibitors (ATRA, tamibaroten, arsenic troxide) for acute promyelocytic leukemia. Int J Clin Oncol 12:313–317PubMedCrossRefGoogle Scholar
  20. 20.
    Miwako I, Kagechika H (2007) Tamibarotene. Drugs Today 43:563–568PubMedCrossRefGoogle Scholar
  21. 21.
    Iwata M, Eshima Y, Kagechika H (2003) Retinoic acids exert direct effects on T cells to suppress Th1 development and enhance Th2 development via retinoic acid receptors. Int Immunol 15:1017–1025PubMedCrossRefGoogle Scholar
  22. 22.
    Cantorna MT, Nashold FE, Hayes CE (1995) Vitamin A deficiency results in a priming environment conducive for Th1 cell development. Eur J Immunol 25:1673–1679PubMedCrossRefGoogle Scholar
  23. 23.
    Hoag KA, Nashold FE, Goverman J, Hayes CE (2002) Retinoic acid enhances the T helper 2 cell development that is essential for robust antibody responses through its action on antigen-presenting cells. J Nutr 132:3736–3739PubMedGoogle Scholar
  24. 24.
    Xiao S, Jin H, Korn T, Liu SM, Oukka M, Lim B et al (2008) Retinoic acid increases Foxp3+ regulatory T cells and inhibits development of Th17 cells by enhancing TGF-beta-driven Smad3 signaling and inhibiting IL-6 and IL-23 receptor expression. J Immunol 181:2277–2284PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Engedal N, Ertesvag A, Blomhoff HK (2004) Survival of activated human T lymphocytes is promoted by retinoic acid via induction of IL-2. Int Immunol 16:443–453PubMedCrossRefGoogle Scholar
  26. 26.
    Ertesvag A, Engedal N, Naderi S, Blomhoff HK (2002) Retinoic acid stimulates the cell cycle machinery in normal T cells: involvement of retinoic acid receptor-mediated IL-2 secretion. J Immunol 169:5555–5563PubMedCrossRefGoogle Scholar
  27. 27.
    Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY (2004) Retinoic acid imprints gut-homing specificity on T cells. Immunity 21:527–538PubMedCrossRefGoogle Scholar
  28. 28.
    Barrington RA, Schneider TJ, Pitcher LA, Mempel TR, Ma M, Barteneva NS et al (2009) Uncoupling CD21 and CD19 of the B-cell coreceptor. Proc Natl Acad Sci USA 106:14490–14495PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Hoshino K, Takeuchi O, Kawai T, Sanjo H, Ogawa T, Takeda Y et al (1999) Cutting edge: toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product. J Immunol 162:3749–3752PubMedGoogle Scholar
  30. 30.
    Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R et al (1995) CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549PubMedCrossRefGoogle Scholar
  31. 31.
    Chen Q, Ross AC (2005) Vitamin A and immune function: retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells. Proc Natl Acad Sci USA 102:14142–14149PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Chen Q, Ross AC (2007) Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4. Cell Immunol 249:37–45PubMedCentralPubMedCrossRefGoogle Scholar
  33. 33.
    Ertesvag A, Aasheim HC, Naderi S, Blomhoff HK (2007) Vitamin A potentiates CpG-mediated memory B-cell proliferation and differentiation: involvement of early activation of p38MAPK. Blood 109:3865–3872PubMedCrossRefGoogle Scholar
  34. 34.
    Xu Z, Pone EJ, Al-Qahtani A, Park SR, Zan H, Casali P (2007) Regulation of aicda expression and AID activity: relevance to somatic hypermutation and class switch DNA recombination. Crit Rev Immunol 27:367–397PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    Watanabe K, Sugai M, Nambu Y, Osato M, Hayashi T, Kawaguchi M et al (2010) Requirement for Runx proteins in IgA class switching acting downstream of TGF-beta 1 and retinoic acid signaling. J Immunol 184:2785–2792PubMedCrossRefGoogle Scholar
  36. 36.
    Nagy L, Szanto A, Szatmari I, Széles L (2012) Nuclear hormone receptors enable macrophages and dendritic cells to sense their lipid environment and shape their immune response. Physiol Rev 92:739–789PubMedCrossRefGoogle Scholar
  37. 37.
    Darmanin S, Chen J, Zhao S, Cui H, Shirkoohi R, Kubo N et al (2007) All-trans retinoic acid enhances murine dendritic cell migration to draining lymph nodes via the balance of matrix metalloproteinases and their inhibitors. J Immunol 179:4616–4625PubMedCrossRefGoogle Scholar
  38. 38.
    Saurer L, McCullough KC, Summerfield A (2007) In vitro induction of mucosa-type dendritic cells by all-trans retinoic acid. J Immunol 179:3504–3514PubMedCrossRefGoogle Scholar
  39. 39.
    Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR et al (2007) Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med 204:1775–1785PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Kuwabara K, Shudo K, Hori Y (1996) Novel synthetic retinoic acid inhibits rat collagen arthritis and differentially affects serum immunoglobulin subclass levels. FEBS Lett 378:153–156PubMedCrossRefGoogle Scholar
  41. 41.
    Zhu L, Bisgaier CL, Aviram M, Newton RS (1999) 9-cis retinoic acid induces monocyte chemoattractant protein-1 secretion in human monocytic THP-1 cells. Arterioscler Thromb Vasc Biol 19:2105–2111PubMedCrossRefGoogle Scholar
  42. 42.
    Mehta K, McQueen T, Tucker S, Pandita R, Aggarwal BB (1994) Inhibition by all-trans-retinoic acid of tumor necrosis factor and nitric oxide production by peritoneal macrophages. J Leukoc Biol 55:336–342PubMedGoogle Scholar
  43. 43.
    Na SY, Kang BY, Chung SW, Han SJ, Ma X, Trinchieri G et al (1999) Retinoids inhibit interleukin-12 production in macrophages through physical associations of retinoid X receptor and NFkappaB. J Biol Chem 274:7674–7680PubMedCrossRefGoogle Scholar
  44. 44.
    Wang X, Allen C, Ballow M (2007) Retinoic acid enhances the production of IL-10 while reducing the synthesis of IL-12 and TNF-alpha from LPS-stimulated monocytes/macrophages. J Clin Immunol 27:193–200PubMedCrossRefGoogle Scholar
  45. 45.
    Montemurro P, Barbuti G, Conese M, Gabriele S, Petio M, Colucci M et al (1999) Retinoic acid stimulates plasminogen activator inhibitor 2 production by blood mononuclear cells and inhibits urokinase-induced extracellular proteolysis. Br J Haematol 107:294–299PubMedCrossRefGoogle Scholar
  46. 46.
    Yamada H, Mizuno S, Ross AC, Sugawara I (2007) Retinoic acid therapy attenuates the severity of tuberculosis while altering lymphocyte and macrophage numbers and cytokine expression in rats infected with Mycobacterium tuberculosis. J Nutr 137:2696–2700PubMedCentralPubMedGoogle Scholar
  47. 47.
    Dzhagalov I, Chambon P, He YW (2007) Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J Immunol 178:2113–2121PubMedCrossRefGoogle Scholar
  48. 48.
    Gu B, Zhu Y, Zhu W, Miao J, Deng Y, Zou S (2009) Retinoid protects rats against neutrophil-induced oxidative stress in acute experimental mastitis. Int Immunopharmacol 9(2):223–229PubMedCrossRefGoogle Scholar
  49. 49.
    Camisa C, Eisenstat B, Ragaz A, Weissmann G (1982) The effects of retinoids on neutrophil functions in vitro. J Am Acad Dermatol 6(4 pt 2 Suppl):620–629PubMedCrossRefGoogle Scholar
  50. 50.
    Bohne M, Struy H, Gerber A, Gollnick H (1997) Effects of retinoids on the generation of neutrophil-derived reactive oxygen species studied by EPR spin trapping techniques. Inflamm Res 46:423–424PubMedCrossRefGoogle Scholar
  51. 51.
    Coble BI, Dahlgren C, Molin L, Stendahl O (1987) Neutrophil function in psoriasis: effects of retinoids. Acta Derm Venereol 67:481–490PubMedGoogle Scholar
  52. 52.
    Yipp BG, Kubes P (2013) NETosis: how vital is it? Blood 122:2784–2794PubMedCrossRefGoogle Scholar
  53. 53.
    Brinckerhoff CE, Coffey JW, Sullivan AC (1983) Inflammation and collagenase production in rats with adjuvant arthritis reduced with 13-cis-retinoic acid. Science 221:756–758PubMedCrossRefGoogle Scholar
  54. 54.
    Trentham DE, Brinckerhoff CE (1982) Augmentation of collagen arthritis by synthetic analogues of retinoic acid. J Immunol 129:2668–2672PubMedGoogle Scholar
  55. 55.
    Nozaki Y, Yamagata T, Yoo BS, Sugiyama M, Ikoma S, Kinoshita K et al (2005) The beneficial effects of treatment with all-trans-retinoic acid plus corticosteroid on autoimmune nephritis in NZB/WF mice. Clin Exp Immunol 139:74–83PubMedCentralPubMedCrossRefGoogle Scholar
  56. 56.
    Kagechika H, Shudo K (2005) Synthetic retinoids: recent developments concerning structure and clinical utility. J Med Chem 48:5875–5883PubMedCrossRefGoogle Scholar
  57. 57.
    Kinoshita K, Kishimoto K, Shimazu H, Nozaki Y, Sugiyama M, Ikoma S et al (2010) Successful treatment with retinoids in patients with lupus nephritis. Am J Kidney Dis 55:344–347PubMedCrossRefGoogle Scholar
  58. 58.
    Ikeda T, Uede K, Hashizume H, Furukawa F (2004) The vitamin A derivative etretinate improves skin sclerosis in patients with systemic sclerosis. J Dermatol Sci 34:62–66PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Yoshishige Miyabe
    • 1
  • Chie Miyabe
    • 1
  • Toshihiro Nanki
    • 2
  1. 1.Division of Rheumatology, Allergy and Immunology, Center for Immunology and Inflammatory Disease, Massachusetts General HospitalHarvard Medical SchoolCharlestownUSA
  2. 2.Department of Clinical Research MedicineTeikyo UniversityItabashi-kuJapan

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