REVIEW article
Front. Immunol.
Sec. Cytokines and Soluble Mediators in Immunity
Cytokine-inducible SH2 domain containing protein (CISH): a versatile negative regulator of cytokine receptor signaling
Wasan Naser 1
Alister Curtis Ward 2
1. University of Baghdad College of Science, Baghdad, Iraq
2. Deakin University, Geelong, Australia
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Abstract
Cytokine-inducible SH2 domain protein (CISH) was the founding member of the suppressor of cytokine signaling (SOCS) family of negative regulators. However, the subsequent elucidation of the physiological roles of CISH has been a slow process, reflecting its often subtle basal functions. Here we provide a narrative review of the literature highlighting the niche roles played by CISH principally in the control of cytokine signaling that impacts immune, blood and other cells. CISH regulates T cell production, polarization and activation through interleukin (IL)-2, IL-4 and the T cell receptor (TCR), natural killer (NK) cell production and activation via IL-15, generation and/or activation of neutrophil, dendritic cell (DC) and macrophage populations via granulocyte-macrophage colony-stimulating factor (GM-CSF), erythrocyte production via erythropoietin (EPO), and appetite control through leptin. Many of these roles are performed by CISH in concert with other SOCS proteins, providing additional complexity. CISH has also been identified in the etiology of several human diseases, particularly immune disorders, such as allergy and susceptibility to infectious disease, as well as a potential target to augment immunotherapy.
Summary
Keywords
CISH, cytokine receptor signaling, Erythropoietin, GM-CSF, IL-15, IL-2, IL-4, Leptin
Received
24 November 2025
Accepted
18 February 2026
Copyright
© 2026 Naser and Ward. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Alister Curtis Ward
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.