Attenuating Janus Kinases (JAK) by Tofacitinib Effectively Prevented Psoriasis Pathology in Various Mouse Skin Inflammation Models

Background: Tofacitinib is a Janus kinase (JAK) inhibitor that preferentially inhibits signaling by JAK1 and JAK3 that blocks the signaling of type I interferons, IL-6 as well as IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Together these cytokines are important to lymphocyte function and therefore regulate multiple aspects of the immune response. Tofacitinib has demonstrated efficacy in clinical trials of various autoimmune diseases including psoriasis.Objectives: To understand the mechanisms of action of tofacitinib in improving psoriasis.Methods: Tofacitinib was evaluated in several IL-23/Th17 pathway-dependent, psoriasis-like skin inflammation models.Results: We demonstrate that similar to mice that received mouse IL-12/23 p40 antibody (anti-p40), treatment with tofacitinib also reduced clinical signs of skin inflammation. Histologic analysis confirmed the clinical data: skin inflammation, the number of cells expressing pSTAT3 were significantly decreased in affected skin of mice treated with tofacitinib and with anti-p40 Ab relative to vehicle/isotype-treated mice. Gene expression analysis of the affected skin revealed that tofacitinib also significantly down-modulated various pro-inflammatory mediators including CXCL10, IL-1β, IL-6, IL-7, IL-17A, IL-22 and S100A8.Conclusion: These results suggest the mechanism of action of tofacitinib is likely due to its ability to block multiple cytokines and attenuate immune response that contribute to the positive clinical efficacy in psoriasis.