Cytokine inducible SH2-containing protein: a versatile negative regulator of cytokine receptor signaling

Cytokine inducible SH2-containing 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 through 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.