Mechanisms that mediate the secretion of chemokines by human microglia: Implications for HIV -1 encephalitis and multiple sclerosis
Chemokines, chemotactic cytokines, recruit leukocytes to sites of injury, and therefore play a critical role in several CNS inflammatory diseases, including HIV-1 encephalitis and multiple sclerosis. Microglia are the resident phagocytes of the brain and are an important source of chemokines. To understand the mechanisms that mediate microglial secretion of chemokines, we tested several factors that are present in the CNS during these two disease processes for their abilities to induce chemokines. Among the factors tested are CD40 ligand, the HIV-1 transactivator protein, Tat, and the HIV-1 envelope protein, gp120.;CD40 is a protein present on microglial cells, and can be upregulated by interferon-gamma, which is secreted by T cells. The ligand for CD40, CD40L, is found on CD4+ T cells and monocytes, both of which have been found in the brain during inflammation. We demonstrated that CD40 is upregulated in HIV-1 encephalitic brains. It has also been shown that CD40 and CD40L are present in the CNS of individuals with MS. We demonstrated that CD40-CD40L interactions lead to the secretion of MCP-1, IP-10, IL-8, MIP-1alpha, MIP-1beta, and RANTES from cultured microglia. MCP-1 and IL-8 secretion is dependent on the ERK1/2 MAPK pathway, and IP-10 secretion is dependent on the p38 MAPK pathway.;Treatment of microglia with Tat results in increased secretion of MCP-1, IP-10, IL-8, MIP-1alpha, MIP-1beta, and RANTES. Similar to CD40L-induced chemokine secretion, Tat-induced chemokine secretion appears to be differentially regulated. MCP-1 and MIP-1beta are mediated through the ERK1/2 MAPK pathway and the phosphatidylinositol-3-kinase pathway (PI3K), IL-8 and MIP-1alpha are mediated through the p38 MAPK pathway, while IP-10 is mediated through the ERK1/2 MAPK pathway, the p38 MAPK pathway, as well as the PI3K pathway. Interestingly, RANTES was not mediated by any of the three pathways tested. Gp120 also induces secretion of chemokines from microglia.;Thus, microglia secrete chemokines in response to CD40 ligation as well as HIV-1 proteins. These chemokines are then able to facilitate the migration of inflammatory cells (both HIV-1 infected and uninfected) into the brain. This influx of cells can promote HIV-1 infection of the CNS as well as amplify the inflammatory cascade that characterizes CNS diseases such as HIV-1 encephalitis and multiple sclerosis.
Source: Dissertation Abstracts International, Volume: 63-03, Section: B, page: 1286.;Advisors: Joan W. Berman.