Up-regulation of receptor antagonist interleukin-1 family members in psoriasis and their regulation by pro-inflammatory cytokines

Abstract

Psoriasis is a chronic inflammatory skin disorder currently regarded an immune disease mediated by interplay between keratinocytes (KCs) and mononuclear leukocytes. T helper (Th) 1 cells were originally viewed as the key player by producing interferon (IFN)-γ and tumor necrosis factor (TNF)-α under the influence of interleukin (IL)-12 [ [1] Schlaak J.F. Buslau M. Jochum W. Hermann E. Girndt M. Gallati H. et al. T cells involved in psoriasis vulgaris belong to the Th1 subset. J. Invest. Dermatol. 1994; 102: 145-149 Abstract Full Text PDF PubMed Google Scholar ]. Proven efficacy of blockers of TNF-α and IFN-γ still emphasizes their contribution in the psoriasis pathogenesis [ 2 Roubille C. Richer V. Starnino T. McCourt C. McFarlane A. Fleming P. et al. The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann. Rheumatic Dis. 2015; 74: 480-489 Crossref PubMed Scopus (543) Google Scholar , 3 Harden J.L. Johnson-Huang L.M. Chamian M.F. Lee E. Pearce T. Leonardi C.L. et al. Humanized anti-IFN-gamma (HuZAF) in the treatment of psoriasis. J. Allergy Clin. Immunol. 2015; 135: 553-556 Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar ]. However, Th17 cells and their cytokines, including IL-17A and IL-22, are now known to be crucial in psoriasis [ [4] Burgler S. Ouaked N. Bassin C. Basinski T.M. Mantel P.Y. Siegmund K. et al. Differentiation and functional analysis of human T(H) 17 cells. J. allergy Clin. Immunol. 2009; 123: e581-e587 Abstract Full Text Full Text PDF PubMed Scopus (94) Google Scholar ]. Targeted antagonists of IL-17A greatly improved moderate to severe plaque psoriasis [ [5] Thaci D. Blauvelt A. Reich K. Tsai T.F. Vanaclocha F. Kingo K.et al. Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe plaque psoriasis: CLEAR, a randomized controlled trial. J. Am. Acad. Dermatol. 2015; 73: 400-409 Abstract Full Text Full Text PDF PubMed Scopus (428) Google Scholar ]. IL-1 family is a set of structurally related molecules mediating innate immunity and inflammation [ [6] Sims J.E. Smith D.E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 2010; 10: 89-102 Crossref PubMed Scopus (1001) Google Scholar ]. Differentiation of Th17 cells require IL-1, and IL-17 in turn, acts on KCs to produce more IL-1 cytokines, several of which were highly expressed in the psoriatic skin and serum [ 6 Sims J.E. Smith D.E. The IL-1 family: regulators of immunity. Nat. Rev. Immunol. 2010; 10: 89-102 Crossref PubMed Scopus (1001) Google Scholar , 7 Balato A. Schiattarella M. Lembo S. Mattii M. Prevete N. Balato N. et al. Interleukin-1 family members are enhanced in psoriasis and suppressed by vitamin D and retinoic acid. Arch. Dermatol. Res. 2013; 305: 255-262 Crossref PubMed Scopus (47) Google Scholar , 8 Carrier Y. Ma H.L. Ramon H.E. Napierata L. Small C. O'Toole M. et al. Inter-regulation of Th17 cytokines and the IL-36 cytokines in vitro and in vivo: implications in psoriasis pathogenesis. J. Invest. Dermatol. 2011; 131: 2428-2437 Abstract Full Text Full Text PDF PubMed Scopus (317) Google Scholar , 9 Johnston A. Xing X. Guzman A.M. Riblett M. Loyd C.M. Ward N.L. et al. IL-1F5, -F6, -F8, and -F9: a novel IL-1 family signaling system that is active in psoriasis and promotes keratinocyte antimicrobial peptide expression. J. Immunol. 2011; 186: 2613-2622 Crossref PubMed Scopus (245) Google Scholar ]. One of the negative regulators to tightly control the IL-1 system is receptor antagonists (RAs), including IL-1Ra, IL-36Ra, and IL-38. As systemic pro-inflammatory cytokines are major participants recruited to the inflammation sites in psoriasis, exploring the systemic expression and regulation of their counter-mechanism would give us clues to control of psoriasis. Although the increased expressions of IL-1 family RAs in psoriatic epidermis have been reported, their circulating levels are still poorly understood. Hence, we evaluated whether IL-1 family RAs are increased in peripheral blood mononuclear cells (PBMCs) of psoriasis patients, and investigated their regulation by the Th1 and Th17 cytokines in PBMCs and KCs.