Involvement of IL-17F via the induction of IL-6 in psoriasis

Abstract

Recently, the important role of T helper 17 (Th17) cells in psoriasis has been clarified; however, the role of IL-17F produced by Th17 cells is still not fully understood. IL-6 exhibits multiple biologic functions, such as regulation of immunological responses including those in psoriatic reactions. Therefore, we examined the production of IL-6 protein in normal human epidermal keratinocytes (NHEKs) stimulated by IL-17F, TNF-alpha, IL-17A, and IL-17A in combination with TNF-alpha, and PBS control. We then examined the expression of IL-6 mRNA in mouse skin after intradermal injection of IL-17F. Finally, IL-17F expression in skin biopsy specimens from psoriasis patients was examined by immunohistochemistry. The results showed that IL-17F induced production of IL-6 in NHEKs in a time-dependent manner. This could be attenuated by chimeric inhibitor blocking the IL-17 receptor. The amounts of IL-6 stimulated by IL-17F were much higher than those stimulated by TNF-alpha or IL-17A. IL-6 was also significantly upregulated via synergistic stimulation with IL-17A plus TNF-alpha. The expression of IL-6 mRNA 24 h after IL-17F injection in the mouse skin was 3.2-fold higher than that in the control group. Immunohistochemistry of inflammatory cells in the dermis demonstrated a large number of CD4(+) T cells showing IL-17F positivity in psoriatic skin lesions, but few or none in non-lesional psoriatic skin. Our results indicate that IL-17F produced by CD4(+) T cells causes the inflammation in psoriasis partly through induction of IL-6 in keratinocytes.

Dual Inhibition of TNFR1 and IFNAR1 in Imiquimod-Induced Psoriasiform Skin Inflammation in Mice

“…This is very interesting, because the complex biology underlying a disease is often multifactorial and requires a multifaceted approach, which can be achieved by combination therapies. Blocking both TNFR1 and IFNAR1 reduces activation of the IL-23/IL-17 axis during IMQ-mediated skin inflammation through reduction of IL-12p40 and IL-17F levels, two novel drug targets in psoriasis, Crohn's disease, and rheumatoid arthritis (34,(64)(65)(66)(67)(68)(69).…”

Tumor Necrosis Factor-associated Palmoplantar Pustular Psoriasis Treated with Interleukin 6 Blocker

“…Fujishima and colleagues reported another indirect mechanism by which CD4+ T lymphocytes may cause inflammation by IL-6 in patients with psoriasis through Th17 cells 8 . These produce IL-17A, IL-17F, and IL-22 and may play an essential role in psoriasis.…”

“…These produce IL-17A, IL-17F, and IL-22 and may play an essential role in psoriasis. IL-17F acts as a selective neutrophil attractant in psoriasis 8 . IL-17F produced by CD4+ T cells may cause inflammation in psoriasis partly through induction of IL-6 in keratinocytes 8 .…”

“…IL-17F acts as a selective neutrophil attractant in psoriasis 8 . IL-17F produced by CD4+ T cells may cause inflammation in psoriasis partly through induction of IL-6 in keratinocytes 8 . In agreement with this, recent studies of Th17 cells have already led to successful therapeutic strategies for psoriasis 9 .…”

Pathogenesis of Psoriasis: The Role of Pro-Inflammatory Cytokines Produced by Keratinocytes

“…Koebner phenomenon is likely to result from the increased activity of IL-6 and its receptor in psoriasis (Grossman et al, 1989). Many studies show that IL-17F is able to induce IL-6 production both in normal human epidermal keratinocytes and in mouse skin (Fujishima et al, 2010). Moreover CD4+ T cells in skin from psoriasis patients express IL-17F and recent studies have demonstrated increased expression of IL-6 in IL-17F-overexpressing mice, thus further supporting a role of IL-17F in the induction of IL-6 (Hurst et al, 2002;Yang et al, 2008).…”