Heat Shock Protein 60 Activates Cytokine-Associated Negative Regulator Suppressor of Cytokine Signaling 3 in T Cells: Effects on Signaling, Chemotaxis, and Inflammation

• Published in: The Journal of immunology (1950) 2005-07, Vol.175 (1), p.276-285
• Main Authors: Zanin-Zhorov, Alexandra, Tal, Guy, Shivtiel, Shoham, Cohen, Michal, Lapidot, Tsvee, Nussbaum, Gabriel, Margalit, Raanan, Cohen, Irun R, Lider, Ofer
• Format: Article
• Language: English
• Subjects: Adoptive Transfer; Animals; Cell Polarity - drug effects; Chaperonin 60 - pharmacology; Chemokine CXCL12; Chemokines, CXC - pharmacology; Chemotaxis, Leukocyte - drug effects; Cytokines - metabolism; Female; Focal Adhesion Kinase 2; Gene Silencing; Humans; In Vitro Techniques; Inflammation - etiology; Inflammation - immunology; Lymphocyte Activation - drug effects; MAP Kinase Signaling System - drug effects; Membrane Glycoproteins - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Models, Immunological; Myosin Light Chains - metabolism; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptors, Cell Surface - metabolism; Receptors, Immunologic - metabolism; Recombinant Proteins - pharmacology; Repressor Proteins - antagonists & inhibitors; Repressor Proteins - genetics; Repressor Proteins - metabolism; Signal Transduction - drug effects; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; T-Lymphocytes - physiology; Toll-Like Receptor 2; Toll-Like Receptors; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.1.276

Previously, we reported that treatment of T cells with the 60-kDa heat shock protein (HSP60) inhibits chemotaxis. We now report that treatment of purified human T cells with recombinant human HSP60 or its biologically active peptide p277 up-regulates suppressor of cytokine signaling (SOCS)3 expression via TLR2 and STAT3 activation. SOCS3, in turn, inhibits the downstream effects of stromal cell-derived-1alpha (CXCL12)-CXCR4 interaction in: 1) phosphorylation of ERK1/2, Pyk2, AKT, and myosin L chain, required for cell adhesion and migration; 2) formation of rear-front T cell polarity; and 3) migration into the bone marrow of NOD/SCID mice. HSP60 also activates SOCS3 in mouse lymphocytes and inhibits their chemotaxis toward stromal cell-derived factor-1alpha and their ability to adoptively transfer delayed-type hypersensitivity. These effects of HSP60 could not be attributed to LPS or LPS-associated lipoprotein contamination. Thus, HSP60 can regulate T cell-mediated inflammation via specific signal transduction and SOCS3 activation.