The investigator seeks to understand the cellular mechanisms of immune and inflammatory responses within the central nervous system (CNS). Elevated expression of the cytokine interleukin-6 (IL-6) within the CNS occurs in injury, infection, stroke, and inflammation. The physiological function of IL-6 within the CNS is complex; IL-6 exerts neuroprotective effects, and yet can also function as a mediator of inflammation, demyelination and astrogliosis, depending on the cellular context. The predominant CNS source of IL-6 is the activated astrocyte. IL-6 acts on cells through interaction with a ligand specific receptor (IL-6R), and then induces signaling by association with gp 130, the signal transducing receptor. The ligand specific IL-6R can function in both a membrane-bound and soluble form (sIL-6R). Importantly, the sIL-6R functions as an agonist; the ability of sIL-6R to confer IL-6 responsiveness to cells devoid of the membrane-bound IL-6R, but expressing gp 130, is referred to as trans-signaling. The investigators recently demonstrated that astrocytes lack sufficient membrane-bound IL-6Rs to transmit IL-6 induced signals, and the inclusion of sIL-6R renders these cells responsive to IL-6. One of the responses elicited by IL-6/sIL-6R is the autoregulation of IL-6 gene expression. In addition, they have made the novel observation that Oncostatin M (OSM), a member of the IL-6 family of cytokines that also utilizes gp130 for signaling, is a potent activator of IL-6 in astrocytes. The investigators hypothesize that IL-6, the sIL-6R and OSM function in a complex cytokine circuitry on astrocytes, eliciting production of IL-6 in the CNS, which can then further activate diverse biological effects ranging from neuroprotection to inflammation. Clearly, then, it is important to identify CNS sources of sIL-6R since its presence can potentiate IL-6 mediated physiological responses. In this application, they will identify the source(s) of the sIL-6R within the CNS; the mechanisms by which the sIL-6R is produced in this site; and the functional significance of sIL-6R (Aim 1).
In Aim 2, they will analyze how IL-6 gene expression in astrocytes is regulated by two novel mediators: IL-6sIL-6R complexes and OSM. In particular, the involvement of two major signaling pathways (JAK/STAT and MAPK) will be investigated. The molecular basis by which IL-6sIL-6R and OSM induce IL-6 transcription in astrocytes will be determined in Aim 3. Therapeutic strategies to enhance the neuroprotective effects of IL-6 via the sIL-6R will be of great utility in diseases such as stroke, while diminution of IL-6 effects will be of benefit in CNS inflammatory diseases such as Multiple Sclerosis. The findings forthcoming from the proposed studies will provide the first biological assessment of sIL-6R production within the brain, thereby setting the foundation for futuretherapeutic manipulation of this critical soluble receptor.
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