Ivashkiv, L. B. 2008. A signal switch hypothesis for cross-regulation of cytokine and TLR signalling pathways. Nature Rev. Immunology. 8:816-822. NIHMSID #72160
Hu, X., A. Chung, I. Wu, J. Foldi, J. Chen, J.-D.Ji, T. Tateya, Y. J. Kang, J. Han, M. Gessler, R. Kageyama and L. B. Ivashkiv. 2008. Selective and Reciprocal Regulation of TLR-inducible Gene Subsets by Notch and IFN-g Pathways. Immunity. 29:691-703. NIHMSID # 77245
Hu, X., S. D. Chakravarty and L. B. Ivashkiv. 2008. Regulation of IFN and TLR signaling during macrophage activation by opposing feedforward and feedback inhibition mechanisms. Immunol. Rev. (In Press). NIHMSID #71125
For more publications, please see the PubMed listing.
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by the anti-inflammatory cytokine interleukin-10 (IL-10) is suppressed in rheumatoid arthritis (RA), such that IL-10 is no longer active.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.