Class II MHC antigens regulate the immune response by presenting antigen to CD4+ T cells, leading to their activation. The expression of class II MHC genes is regulated by a non-DNA binding protein, class II transactivator (CIITA) the """"""""master control factor"""""""" for class II MHC transcription. Appropriate constitutive and inducible expression of class II MHC antigens is essential for normal immune function, while aberrant expression has been correlated with autoimmune diseases, including multiple sclerosis. The costimulatory molecule, CD40, upon interaction with its cognate ligand CD154 on T cells, promotes the expression of numerous cytokines/chemokines by the CD40 expressing cells. In the inflamed CNS, class II MHC and CD40 molecules are aberrantly expressed by microglia and macrophages, allowing them to function as antigen presenting cells. This leads to activation of autoreactive CD4+ T cells, and subsequent inflammation and demyelination. IFNgamma is the most potent inducer of class II MHC and CD40 expression, and plays a pivotal role in the initiation of intracerebral immune responses. We hypothesize that aberrant CIITA, class II MHC and CD40 expression in microglia/macrophages results in detrimental immunologic activities in the CNS. As a corollary, we propose that downregulation of these molecules will result in a reduction of immune responsiveness in the CNS. Restricting expression of class II MHC and CD40 molecules in the CNS can be achieved by a new family of proteins termed Suppressors of Cytokine Signaling (SOCS). SOCS proteins function as negative regulators of cytokine signaling, especially those such as IFNgamma that utilizes the JAK/STAT pathway. Currently, there is no information regarding the expression or function of SOCS proteins within the CNS. In this study, we will examine the ability of microglia/macrophages to express SOCS proteins, both constitutive and cytokine-inducible expression (AIM 1). Next, SOCS gene expression in MS brain will be examined (AIM 2). We will determine the cellular localization of SOCS proteins within the CNS, the disease specificity of SOCS expression, and the extent of SOCS expression in different stages of MS lesions. Lastly, the ability of SOCS proteins to modulate IFNgamma-induction of class II MHC and CD40 in microglia/macrophages will be tested by stable transfection of SOCS-1 and SOCS-3 proteins in these cells (AIM3). Our studies will provide the first biological assessment of SOCS production and function in cells of the CNS, thereby setting the foundation for future therapeutic manipulations of these critical immunoregulatory proteins.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (04))
Program Officer
Behar, Toby
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Alabama Birmingham
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Zheng, Ying; Qin, Hongwei; Frank, Stuart J et al. (2011) A CK2-dependent mechanism for activation of the JAK-STAT signaling pathway. Blood 118:156-66
Akhtar, Lisa Nowoslawski; Qin, Hongwei; Muldowney, Michelle T et al. (2010) Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages. J Immunol 185:2393-404
Qin, Hongwei; Niyongere, Sandrine A; Lee, Sun Jung et al. (2008) Expression and functional significance of SOCS-1 and SOCS-3 in astrocytes. J Immunol 181:3167-76
Baker, Brandi J; Qin, Hongwei; Benveniste, Etty N (2008) Molecular basis of oncostatin M-induced SOCS-3 expression in astrocytes. Glia 56:1250-62
Lee, Sun Jung; Qin, Hongwei; Benveniste, Etty N (2007) Simvastatin inhibits IFN-gamma-induced CD40 gene expression by suppressing STAT-1alpha. J Leukoc Biol 82:436-47
Qin, Hongwei; Roberts, Kevin L; Niyongere, Sandrine A et al. (2007) Molecular mechanism of lipopolysaccharide-induced SOCS-3 gene expression in macrophages and microglia. J Immunol 179:5966-76
Nozell, Susan; Laver, Travis; Patel, Kiran et al. (2006) Mechanism of IFN-beta-mediated inhibition of IL-8 gene expression in astroglioma cells. J Immunol 177:822-30
Qin, Hongwei; Wilson, Cynthia A; Lee, Sun Jung et al. (2006) IFN-beta-induced SOCS-1 negatively regulates CD40 gene expression in macrophages and microglia. FASEB J 20:985-7
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
Qin, Hongwei; Wilson, Cynthia A; Lee, Sun Jung et al. (2005) LPS induces CD40 gene expression through the activation of NF-kappaB and STAT-1alpha in macrophages and microglia. Blood 106:3114-22

Showing the most recent 10 out of 39 publications