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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039954-02
Application #
6394354
Study Section
Special Emphasis Panel (ZRG1-BDCN-4 (01))
Program Officer
Behar, Toby
Project Start
2000-04-01
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
2
Fiscal Year
2001
Total Cost
$287,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
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Adamski, Jill; Benveniste, Etty N (2005) 17beta-estradiol activation of the c-Jun N-terminal kinase pathway leads to down-regulation of class II major histocompatibility complex expression. Mol Endocrinol 19:113-24
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Ma, Zhendong; Chang, Mi Jung; Shah, Reesha et al. (2004) Brg-1 is required for maximal transcription of the human matrix metalloproteinase-2 gene. J Biol Chem 279:46326-34
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Benveniste, Etty N; Nguyen, Vince T; Wesemann, Duane R (2004) Molecular regulation of CD40 gene expression in macrophages and microglia. Brain Behav Immun 18:7-12
Chen, Shao-Hua; Benveniste, Etty N (2004) Oncostatin M: a pleiotropic cytokine in the central nervous system. Cytokine Growth Factor Rev 15:379-91
Adamski, Jill; Ma, Zhendong; Nozell, Susan et al. (2004) 17beta-Estradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter. Mol Endocrinol 18:1963-74

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