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, genes such as the Fc-gamma receptor I or interferon regulatory factor 1. We are investigating the initiation and regulation of the activation of these genes. We have identified both tyrosine kinases of the Jak family and transcription factors of the STAT family that are required for activation of these genes. We have most recently shown that for IL-10 activation of monocytes and T lymphocytes, the transcription factors, STAT1 and STAT3 are activated as are the tyrosine kinases, tyk2 and Jak1. There is differential activation of the STAT proteins between these two cell types. We have also shown that the STAT proteins and Jak kinases are associated with cytokine receptors. We chose to study the interferon-gamma receptor, since this receptor is well-characterized and we have defined previously in detail the interaction of IFNgamma with its receptor. We showed that Jak1 associates with the alpha chain of the receptor, whereas Jak2 associates with the beta chain of the receptor. Both kinases are required for STAT1 activation, which also was shown to associate with the alpha chain of the receptor. We are also studying the activation of STAT5 by GMCSF and IL-2. Growth factors such as GMCSF are important for monocyte development and survival in addition to their activation. 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. The role of the different STAT5 proteins on transcription and the contribution of cell type specific pathways leading to their activation is being studied.
