Nitric oxide (NO) is the principal mediator of many of the cytokine-inducible macrophage activities during a cell-mediated immune response, including the killing of infectious pathogens and tumor cells. However, elevated levels of NO have been associated with a number of common chronic inflammatory diseases such as diabetes, rheumatoid arthritis, asthma and inflammatory bowel disease. Thus, regulation of NO synthesis by activated macrophages is critical to maintaining a balance between an effective immune response and tissue-damaging inflammation and cell death. This balance is achieved by a complex interplay between positive and negative effectors of macrophage activation. Macrophage-stimulating protein, the ligand for the STK receptor tyrosine kinase, suppresses NO production by IFN-gamma-activated macrophages in vitro. Subsequently, mice lacking the STK receptor exhibit increased inflammation, tissue damage and death following the onset of a cell-mediated immune response. The proposed studies will explore the mechanism by which the STK receptor regulates macrophage activation and NO production using a combination of biological, biochemical and genetic analyses. First, IFN-gamma-activated macrophages from the STK knockout mice will be used to further examine the effect the absence of the STK receptor has on the activation of macrophages both in vitro and in vivo. Second, macrophage cell lines expressing the STK receptor will be generated in order to study the signaling properties of STK in the context of macrophage activation, and the mechanism by which it alters the response of these cells to IFN-gamma. Finally, the STK deficient mice will be crossed with knockouts of other known regulators of macrophage activation, starting with the interferon gamma receptor, as well as mice lacking inducible nitric oxide synthase (iNOS). Macrophages from these mice will be studied to determine which signals lie in the same pathway, and how these signals intersect. By understanding, in more detail, the regulation of macrophage activation, the PI hopes to begin to identify targets for suppression of the tissue-damaging effects of inflammation without compromising the host immune response.
| Sharda, Daniel R; Yu, Shan; Ray, Manujendra et al. (2011) Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. J Immunol 187:2181-92 |
