Interferons, cytokines such as IL-4, IL-6, and IL-10, and hematopoietic growth factors such as granulocyte-macrophage colony stimulating factor (GMCSF) play critical roles in the initiation, promulgation, and resolution of chronic inflammation. One of the more important processes in chronic immune inflammation is cell mediated immunity, of which the primary cell type is the monocyte/macrophage. By way of its wide variety of soluble secreted mediators, the macrophage becomes an important player in mediating TH1 type responses. One of the predominant cytokines characteristic of this response is interferon-gamma (IFN). The other T cell response, TH2, is characterized by secretion of cytokines such as IL-4 and IL-10. In addition, growth factors such as GMCSF give cells such as macrophages and neutrophils a survival advantage in sites of inflammation. Clearly, understanding how these cytokines and interferons interact to modulate cell functions is critical to potential manipulations that would allow better control of chronic inflammation. We have focused on the interactions of IFNs and cytokines with peripheral blood monocytes and lymphocytes, and how these cells modulate the expression of various early response genes that we think are critical to maintaining chronic immune inflammation. We are characterizing the ability of IL-10 to inhibit IFN induced genes. We have shown that IL-10 can reduce the mRNA levels of two IFN specific genes. We are currently defining where in the signal transduction pathway this inhibition occurs. We have continued our studies on the signal transduction pathway thorugh the IFNgamma receptor. We are currently characterizing the role of the MAP kinase and raf1 pathways in this cascade by using cells that are deficient for Jak1 and/or Jak2 tyrosine kinases. We have shown that Jak1 is necessary for the activation of raf1 by IFNgamma. We are also studying the activation of STAT5 by GMCSF and IL-2. We have shown that GMCSF activates both STAT5a and STAT5b and that an 80 kDa product of the STAT5 proteins binds to the GAS element found in the promoters of many cytokine induced early response genes. We have also shown that heterodimers of STAT5a and STAT5b form in response to both GMCSF and IL-2. We are characterizing the STAT5 response following treatment with IL-2 in human lymphoblasts. We are exploring the role of STAT5 in myeloid development and differentiation along with activation in studies with Dr. Hennighausen on the STAT5a null mouse. We are also studying the role of the Jak/STAT pathway in patients with the inflammatory diseases, systemic lupus erythematosus and rheumatoid arthritis and have observed a difference in the ability of cells from these patients to respond to IFNalpha when compared to normal controls. All these studies in addition to studies in an animal model of immune complex mediated inflammation will enhance our understanding of the role of cytokine activated Jak/STAT pathway in chronic inflammatory diseases.
