IFN-α Finds Its SOCS

Abstract

One of the treatments for patients with metastatic malignant melanoma is interferon-α (IFN-α); however, the success rate is only 10 to 15%. Previous studies suggest that IFN-α treatment of T cell lines leads to increased production of members of the suppressor of cytokine signaling (SOCS) family of proteins, which are well characterized in their ability to inhibit cytokine signaling. SOCS1 and SOCS3 inhibit IFN-α-mediated signal transduction. Zimmerer et al. investigated the effect of IFN-α treatment on the abundance of SOCS mRNAs and proteins in primary cells from healthy donors and patients with metastatic melanoma. Real-time polymerase chain reaction analysis revealed that peripheral blood mononuclear cells (PBMCs) from healthy donors treated in vitro with IFN-α had increased amounts of mRNAs for SOCS1, SOCS2, SOCS3, and the SOCS family member, cytokine-inducible Src homology 2 (SH2)-containing protein (CIS). Western blot analysis of immunoprecipitates from PBMCs showed that the abundance of these SOCS family members was also increased after IFN-α treatment. Further cell-specific analyses demonstrated that the strongest effect of IFN-α treatment was found within T cells. Analysis of PBMCs from patients with metastatic melanoma 1 hour after intravenous administration of IFN-α showed increased amounts of the mRNAs for some SOCS family members analyzed in healthy donors. Treatment of SOCS1-deficient mice (in a mouse model of malignant melanoma) with IFN-α reduced tumors in 70% of mice, without side effects, whereas all of the IFN-α-treated wild-type mice died. These data suggest that modulating SOCS activity in the context of cytokine treatment may improve clinical outcome. J. M. Zimmerer, G. B. Lesinski, S. V. Kondadasula, V. I. Karpa, A. Lehman, A. RayChaudhury, B. Becknell, W. E. Carson III, IFN-α-induced signal transduction, gene expression, and antitumor activity of immune effector cells are negatively regulated by suppressor of cytokine signaling proteins. J. Immunol. 178 , 4832-4845 (2007). [PubMed]