Effect of methotrexate on the serum levels of IL-22 in Patients with moderate to severe plaque-type psoriasis

Jitlada Meephansan; Jongkonnee Wongpiyabovorn; Wannasri Sindhuphak

Authors

Jitlada Meephansan DIVISION OF DERMATOLOGY, DEPARTMENT OF MEDICINE, FACULTY OF MEDICINE, CHULALONGKORN UNIVERSITY, BANGKOK, THAILAND
Jongkonnee Wongpiyabovorn DIVISION OF DERMATOLOGY, DEPARTMENT OF MEDICINE, FACULTY OF MEDICINE, CHULALONGKORN UNIVERSITY, BANGKOK, THAILAND
Wannasri Sindhuphak DIVISION OF DERMATOLOGY, DEPARTMENT OF MEDICINE, FACULTY OF MEDICINE, CHULALONGKORN UNIVERSITY, BANGKOK, THAILAND

Keywords:

Methotrexate, Psoriasis, Interleukin-22

Abstract

Background: Interleukin 17 (IL-17) and Interleukin-22 (IL-22) are effector molecules of T-helper 17 (Th-17) lineage that responsible for keratinocytes proliferation in psoriasis. Methotrexate has been widely used as first-line treatment in moderate to severe psoriasis. Methotrexate has many mechanisms to inhibit inflammatory responses. But no evidence has shown that methotrexate is able to downregulate Th17 cytokines.

Objective: To compare serum levels of IL-17, IL-22 in patients with moderate to severe plaque type psoriasis before and after treatment with metrotrexate

Methods: Nineteen patients with Psoriasis Area Severity Index (PASI) score ≥ 10 were given methotrexate 15 mg per week up to 12 weeks. Clot blood for measurement of IL-22 by enzyme-linked immunosorbent assay (ELISA: R&D Systems, Minneapolis, MN, USA) was taken before and after treatment.

Results: Eleven of 19 patients [57.8%] achieved 75% PASI score reduction. IL-22 levels were significantly higher in psoriasis patients[56.63±60.73 pg/ml] than in controls[12.58±12.59 pg/ml]. Methotrexate significantly reduced IL-22 levels after therapy [Z=3.5, p<0.001]. A significant positive correlation between IL-22 and PASI was found [r=0.63, p=0.004].

Conclusion: Downregulate IL-22 which is a Th17 cytokines is one possible mechanisms of therapeutic efficacy of methotrexate in psoriasis. IL-22 is may be to be a good biomarker for assessment psoriasis clinical response to methotrexate in Thai populations.

References

Torti DC, Feldman SR. Interleukin-12, interleukin-23, and psoriasis: current prospects. J Am Acad Dermatol 2007; 57: 1059-68.

Boyman O, Conrad C, Tonel G, Gilliet M, Nestle FO. The pathogenic role of tissue-resident immune cells in psoriasis. Trends Immunol 2007; 28: 51-7.

Lew W, Lee E, Krueger JG. Psoriasis genomics: analysis of proinflammatory (type 1) gene expression in large plaque (Western) and small plaque (Asian) psoriasis vulgaris. Br J Dermatol 2004;150: 668-76.

Teunissen MB, Koomen CW, de Waal MR, Wierenga EA, Bos JD. Interleukin-17 and interferon-gamma synergize in the enhancement of proinflammatory cytokine production by human keratinocytes. J Invest Dermatol 1998 Oct;111(4):645-9.

Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol 2005; 6: 1123-32.

Park H, Li Z, Yang XO, Chang SH, Nurieva R, Wang YH, et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol 2005; 6: 1133-41.

Wolk K, Witte E, Wallace E, Docke WD, Kunz S, Asadullah K, et al. IL-22 regulates the expression of genes responsible for antimicrobial defense, cellular differentiation, and mobility in keratinocytes: a potential role in psoriasis. Eur J Immunol 2006; 36: 1309-23.

Wolk K, Sabat R. Interleukin-22: a novel T- and NK-cell derived cytokine that regulates the biology of tissue cells. Cytokine Growth Factor Rev 2006; 17: 367-80.

Kunz S, Wolk K, Witte E, Witte K, Doecke WD, Volk HD, et al. Interleukin (IL)-19, IL-20 and IL-24 are produced by and act on keratinocytes and are distinct from classical ILs. Exp Dermatol 2006 Dec;15(12):991-1004.

Wolk K, Kunz S, Witte E, Friedrich M, Asadullah K, Sabat R. IL-22 increases the innate immunity of tissues. Immunity 2004; 21: 241-54.

Saporito FC, Menter MA. Methotrexate and psoriasis in the era of new biologic agents. J Am Acad Dermatol 2004; 50: 301-9.

Dolhain RJ, Tak PP, Dijkmans BA, De KP, Breedveld FC, Miltenburg AM. Methotrexate reduces inflammatory cell numbers, expression of monokines and of adhesion molecules in synovial tissue of patients with rheumatoid arthritis. Br J Rheumatol 1998; 37: 502-8.

Gerards AH, de LS, de Groot ER, Dijkmans BA, Aarden LA. Inhibition of cytokine production by methotrexate. Studies in healthy volunteers and patients with rheumatoid arthritis. Rheumatology (Oxford) 2003; 42: 1189-96.

Piskin G, Heydendael VM, de Rie MA, Bos JD, Teunissen MB. Cyclosporin A and methotrexate are equally effective in reducing T cell numbers in psoriatic skin lesions but have no consistent effect on IFN-gamma and IL-4 expression in psoriatic skin in situ. Arch Dermatol Res 2003; 294: 559-62.

Sigmundsdottir H, Johnston A, Gudjonsson JE, Bjarnason B, Valdimarsson H. Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin. Exp Dermatol 2004; 13: 426-34.

Torres-Alvarez B, Castanedo-Cazares JP, Fuentes-Ahumada C, Moncada B. The effect of methotrexate on the expression of cell adhesion molecules and activation molecule CD69 in psoriasis. J Eur Acad Dermatol Venereol 2007; 21: 334-9.

Johnston A, Gudjonsson JE, Sigmundsdottir H, Ludviksson BR, Valdimarsson H. The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules. Clin Immunol 2005; 114: 154-63.

Zheng Y, Danilenko DM, Valdez P, Kasman I, Eastham-Anderson J, Wu J, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-23-induced dermal inflammation and acanthosis. Nature 2007; 445: 648-51.

Sabat R, Philipp S, Hoflich C, Kreutzer S, Wallace E, Asadullah K, et al. Immunopathogenesis of psoriasis. Exp Dermatol 2007; 16: 779-98.

Caproni M, Antiga E, Melani L, Volpi W, Del BE, Fabbri P. Serum Levels of IL-17 and IL-22 Are Reduced by Etanercept, but not by Acitretin, in Patients with Psoriasis: a Randomized-Controlled Trial. J Clin Immunol 2008.

Gottlieb AB, Chamian F, Masud S, Cardinale I, Abello MV, Lowes MA, et al. TNF inhibition rapidly down-regulates multiple proinflammatory pathways in psoriasis plaques. J Immunol 2005; 175: 2721-9.

Wilson NJ, Boniface K, Chan JR, McKenzie BS, Blumenschein WM, Mattson JD, et al. Development, cytokine profile and function of human interleukin 17-producing helper T cells. Nat Immunol 2007; 8: 950-7.

Zaba LC, Cardinale I, Gilleaudeau P, Sullivan-Whalen M, Suarez-Farinas M, Fuentes-Duculan J, et al. Amelioration of epidermal hyperplasia by TNF inhibition is associated with reduced Th17 responses. J Exp Med 2007; 204: 3183-94.

Kryczek I, Bruce AT, Gudjonsson JE, Johnston A, Aphale A, Vatan L, et al. Induction of IL-17+ T cell trafficking and development by IFN-gamma: mechanism and pathological relevance in psoriasis. J Immunol 2008; 181: 4733-41.