The Journal of Immunology, 2007, 178: 94.1.
Copyright © 2007 by The American Association of Immunologists, Inc.
Properties of a SOCS-1 small molecule antagonist
Lilian W Waiboci,
Howard M Johnson,
James P Martin and
Chulbul M Ahmed
Microbiology and Cell Science, University of Florida, 981 Museum Rd Rm1052, P.O. Box 110700, Gainesville, FL, 32611-0700
Abstract
Suppressor of cytokine signaling 1 (SOCS-1) is a member of a small family of protein molecules that are regulators of cytokines that signal through JAK2 tyrosine kinase and STAT transcription pathways. SOCS-1 binds to the autophosphorylation site of JAK2 tyrosine kinase and blocks its ability to activate substrates such as STAT1-alpha both directly and by initiation of proteosomal degradation. Thus, SOCS-1 is an attenuator of positive immune regulators such as gamma interferon. We reasoned that a peptide corresponding to the autophosphorylation site of JAK2 in the phosphorylated state, pJAK2(1001–1013), would bind to induced SOCS-1 in cells and block its inhibitory effects on mediators of the immune response. We therefore synthesized pJAK2(1001–1013) with an attached palmitate residue for cell penetration and showed that it enhanced suboptimal IFN-gamma, blocked SOCS-1 induced inhibition of STAT3 phosphorylation in IL-6 treated cells, enhanced IFN-gamma activation site (GAS) promoter activity, and enhanced antigen specific proliferation. In a mouse model of lethal vaccinia virus infection, pJAK2(1001–1013) completely protected mice against an overwhelming lethal dose (106 pfu intranasal) of vaccinia virus. The small molecule SOCS-1 antagonist should be quite useful in enhancing the immune response against infectious agents and cancer.
Supported by NIH grants AI 056152 and NS051245 to HMJ.
