Lionel B. Ivashkiv, MD
Research Description
Cytokine Signaling and Inflammation
Cytokines are secreted proteins that mediate communication between cells. Cytokines trigger signal transduction and gene activation cascades that regulate cellular activation, proliferation, differentiation, and survival. A critical role for cytokines in immunity and inflammation, and in arthritis and autoimmune diseases, is now well established. New biological therapies aimed at neutralizing cytokines have been very successful and have initiated a new era of rational therapy of inflammatory and autoimmune diseases.
Our laboratory studies a major signal transduction pathway utilized by many cytokines, the Janus kinase ¡V signal transducer and activator of transcription (Jak-STAT) pathway. The laboratory is characterizing molecular mechanisms that regulate signaling by the Jak-STAT pathway. We are developing the idea that modulation or ¡§reprogramming¡¨ of cytokine signaling during inflammation is an important determinant of the balance of cytokine action. We are studying the mechanisms and the impact of modulation of cytokine signaling on cell function and gene expression, and on the severity of inflammation and related tissue damage. For example, we have shown that signaling by the anti-inflammatory cytokine interleukin-10 (IL-10) is suppressed in rheumatoid arthritis (RA), such that IL-10 is no longer active. In systemic lupus erythematosus (SLE), IL-10 signaling is reprogrammed such that IL-10 acquires pro-inflammatory functions and thus contributes to inflammation instead of suppressing it. A new area of investigation in our laboratory is the analysis of cytokine regulation of tissue destruction and remodeling.
The laboratory takes an integrated bench to bedside approach and studies signal transduction defects in human disease samples, in defined in vitro systems, and in animal models of arthritis and SLE. Biochemical approaches are complemented by genetic approaches that utilize RNA interference or knockout mice, and by microarray analysis of genome-wide gene expression. The long term goals of our laboratory are to define the molecular basis of the regulation of cytokine signaling during inflammation, and to target signaling pathways as a novel approach to therapy.
Appointments
Senior Scientist and Director of Basic Research, Hospital for Special Surgery
David H. Koch Chair in Arthritis and Tissue Degeneration, Hospital for Special Surgery
Professor of Medicine and Immunology, Weill Medical College of Cornell University
Lionel B. Ivashkiv, MD is the author of the following articles on HSS.edu:
For Professionals
Selected Publications
Carmen Herrero, Xiaoyu Hu, Wai Ping Li, Stuart Samuels, M. Nusrat Sharif, Sergei Kotenko, and L. B. Ivashkiv. 2003. Reprogramming of IL-10 activity and signaling by IFNƒ×. J. Immunol. 171:5034-5041.
Ivashkiv, L.B. and X. Hu. 2003. The Jak-STAT pathway in rheumatoid arthritis: pathogenic or protective? Arth. Rheum. 48:2092-2096.
Ivashkiv, L.B. and I. Tassiulas. 2003. Can SOCS make arthritis better? J. Clin. Invest. 111:795-797.
Tassiulas, I., X. Hu, H. H. Ho, Y. Kashyap, Y. Hu, C. Lowell, and L. B. Ivashkiv. 2004. Amplification of IFNa-induced STAT1 activation and inflammatory function by Syk and ITAM-containing adaptors. Nature Immunology. 5:1181-1189.
Hu, X., H. H. Ho, O. Lou, C. Hidaka, and L. B. Ivashkiv. 2005. Homeostatic role of interferons conferred by inhibition of IL-1-mediated inflammation and tissue destruction. J. Immunol. 175:131-138.
Du, Z., Y. Shen, W. Yang, I. Mecklenbrauker, B. G. Neel, and L. B. Ivashkiv. 2005. Inhibition of IFNa signaling by a PKC- and protein tyrosine phosphatase SHP2-dependent pathway. Proc. Natl. Acad. Sci. USA 102:10267-10272.
For more publications, please see the
PubMed listing.
Clinical Trials
