Background: Anti-tumor necrosis factor (TNF) therapy-induced psoriasiform skin lesions are a recently described side effect in patients with inflammatory bowel disease. Interleukin (IL)-12/IL-23 neutralization is an effective therapy for these lesions. As Th17 cytokines, such as IL-17A, and IL-1 family members, such as IL-36, play a significant role in plaque psoriasis, we analyzed the involvement of IL-17C and IL-36γ in anti-TNF-induced skin lesions of patients with Crohn's disease.
Methods: IL-36γ and IL-17C levels in biopsies of anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease were assessed by immunohistochemical analysis and correlated to additional immunohistochemical data. IL-36γ and IL-17C messenger RNA, protein, and induced gene expression in human primary keratinocytes were analyzed using quantitative real-time polymerase chain reaction, immunoblotting, and enzyme-linked immunosorbent assay.
Results: IL-36γ and IL-17C are increased in anti-TNF-induced psoriasiform skin lesions of patients with Crohn's disease, compared with healthy controls. Epidermal IL-36γ and IL-17C levels strongly correlate with each other (r = 0.748, P = 0.003). In contrast to IL-12 and IL-23, IL-36γ increases the expression of proinflammatory signals and effector molecules of innate immunity in keratinocytes. However, IL-17C affects keratinocyte defensin gene expression only in combination with TNF-α. IL-36γ induces TNF-α expression in keratinocytes and sustains a self-amplifying proinflammatory loop with IL-17C by inducing its own expression and that of IL-17C.
Conclusions: Our study demonstrates a unique role of the previously unknown self-amplifying, proinflammatory IL-36γ/IL-17C loop in the pathogenesis of anti-TNF-induced psoriasiform skin lesions. These findings suggest a beneficial effect of IL-36γ/IL-17C inhibition during anti-TNF-induced psoriasiform lesions in patients with inflammatory bowel disease.