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World J Biol Chem. Jan 27, 2022; 13(1): 1-14
Published online Jan 27, 2022. doi: 10.4331/wjbc.v13.i1.1
Current understanding of the role of tyrosine kinase 2 signaling in immune responses
Ryuta Muromoto, Kenji Oritani, Tadashi Matsuda
Ryuta Muromoto, Tadashi Matsuda, Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
Kenji Oritani, Department of Hematology, International University of Health and Welfare, Narita 286-8686, Japan
Author contributions: Muromoto R, Oritani K and Matsuda T participated sufficiently in this work of drafting the article and/or revising the article for the important rational content; all authors gave final approval of the version to be submitted.
Supported by Grant-in-Aid for scientific research from Ministry of Education, Culture, Sports, Science and Technology of Japan, No. 19H03364 and No. 20K07010.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Tadashi Matsuda, PhD, Professor, Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-ku Kita12 Nishi 6, Sapporo 060-0812, Japan. tmatsuda@pharm.hokudai.ac.jp
Received: March 27, 2021
Peer-review started: March 27, 2021
First decision: July 27, 2021
Revised: August 6, 2021
Accepted: December 22, 2021
Article in press: December 22, 2021
Published online: January 27, 2022
Abstract

Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocyte-mediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice.

Keywords: Tyrosine kinase 2, Cytokines, Signal transduction, Immune system, Inflammation

Core Tip: Studies on murine tyrosine kinase 2 (Tyk2)-deficient models were reviewed to examine the role of Tyk2 dysregulation in human diseases. Tyk2-deficient mice exhibit reduced responses in several interleukin-12 (IL-12)/Th1- and IL-23/Th17-mediated models of diseases, including rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases, psoriasis, sarcoidosis, and delayed-type hypersensitivity. These findings demonstrate a broad contribution of Tyk2 to immune responses. Tyk2 represents a candidate for drug development by targeting both the IL-12/Th1 and IL-23/Th17 axes.