A FAMILY OF CYTOKINE-INDUCIBLE INHIBITORS OF SIGNALING

Cytokines are secreted proteins that regulate important cellular respo nses such as proliferation and differentiation(1). Key events in cytok ine signal transduction are well defined: cytokines induce receptor ag gregation, leading to activation of members of the JAK family of cytop lasmic tyrosine kinases. In turn, members af the STAT family of transc ription factors are phosphorylated, dimerize and increase the transcri ption of genes with STAT recognition sites in their promoters(1-4). Le ss is known of how cytokine signal transduction is switched off. We ha ve cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibit ed both interleukin-6-induced receptor phosphorylation and STAT activa tion. We have also cloned two-relatives of SOCS-1, named SOCS-2 and SO CS-3, which together with the previously described CIS (ref. 5) form a new family of proteins. Transcription of all four SOCS genes is incre ased rapidly in response to interleukin-6, in vitro and in vivo, sugge sting they may act in a classic negative feedback loop to regulate cyt okine signal transduction.