Attenuating Janus Kinases (JAK) by Tofacitinib Effectively Prevented Psoriasis Pathology in Various Mouse Skin Inflammation Models
|Hak-Ling Ma1, Katherine Masek-Hammerman2, Susan Fish1, Lee Napierata1, Eva Nagiec2, Martin Hegen1 and James D Clark1*|
|1Immunoscience Research Unit, Pfizer WR&D., Cambridge, MA, USA|
|2Drug Safety Research & Development, Pfizer WR&D., Cambridge, MA, USA|
|Corresponding Author :||James D Clark, Ph.D
Immunoscience Research Unit, Pfizer W R&D.
200 Cambridge Park Drive, Cambridge, MA 02140, USA
E-mail: [email protected]
|Received September 27, 2013; Accepted December 01, 2013; Published December 08, 2013|
|Citation: Ma HL, Masek-Hammerman K, Fish S, Napierata L, Nagiec E, et al. (2013) Attenuating Janus Kinases (JAK) by Tofacitinib Effectively Prevented Psoriasis Pathology in Various Mouse Skin Inflammation Models. J Clin Cell Immunol 4:176. doi:10.4172/2155-9899.1000176|
|Copyright: © 2013 Ma HL, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.|
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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.