Our goal is to understand the basis of immune and inflammatory responses within the CNS. Immunological activation of macrophages/microglia and astrocytes leads to the production of cytokines that impact on glial and neuronal function. Cytokines have far-reaching effects in the CNS, including the initiation and regulation of immune/inflammatory responses. Macrophages/microglia and astrocytes not only produce cytokines, but also respond to them via cell surface receptors. Macrophage/microglial and astrocytic activation in general is aimed at promoting a beneficial restoration of endangered CNS elements and functions. However, excessive and sustained stimulation of these cells contributes to acute and chronic neuropathologies. Therefore, dysregulation of macrophage/microglial and astrocytic cytokine production and responsiveness may promote direct neurotoxicity, as well as disturb neural cell functions. The biological effects of cytokines are mediated by intracellular signal transduction pathways;the most common being the Janus Kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway (JAK-STAT). Cytokines implicated in CNS pathology include IFN-y, IFN-p and IL-6 family members, all of which signal through the JAK-STAT pathway. A precise regulation of both the magnitude and duration of JAK and STAT activation is essential, as dysregulation of the JAK-STAT pathway has pathological implications. Suppressors of Cytokine Signaling (SOCS) proteins function to inhibit the JAK-STAT pathway. SOCS proteins are inducible by cytokines, and inhibit signaling by directly binding to cytokine receptor chains or associated JAKs to inhibit tyrosine kinase activity, thereby functioning in a negative feedback loop. There is limited information regarding the expression and function of SOCS proteins within the CNS. Our preliminary results indicate that both SOCS-1 and SOCS-3 function to attenuate expression of genes critical for immune/inflammatory responses in macrophages/microglia and astrocytes. We hypothesize that expression of SOCS-1/SOCS-3 will attenuate cytokine-induced inflammatory and immune responses by inhibiting activation of these cells, thereby exerting beneficial effects for immune-mediated CNS diseases. We will examine the ability of astrocytes, microglia and macrophages to express SOCS-1/SOCS-3 proteins in response to CNS-relevant stimuli, and elucidate the transcriptional programs underlying SOCS-1/SOCS-3 gene transcription (Aims 1 and 3). The ability of SOCS-1/SOCS-3 to modulate immunological and inflammatory responses in glial cells and macrophages will also be examined (Aims 2 and 4), using macrophage and astroglial cell lines that express siRNA against SOCS-1/SOCS-3 in an inducible manner. Our proposed studies will provide the first biological assessment of SOCS-1/SOCS-3 production and function in cells of the CNS, thereby providing the basis for future assessment of SOCS-1/SOCS-3 as attenuators of inflammatory and neurotoxic responses in the CNS.
Showing the most recent 10 out of 38 publications
