THE ROLE OF ICSBP IN MUCOSAL IMMUNE RESPONSE

$202,134P01FY2008DKNIH

Icahn School Of Medicine At Mount Sinai, New York NY

Investigators

Linked publications & trials

Paper 34887354 Paper 30169459 Paper 30145369 Paper 30136242 Paper 30136234 Paper 30136230 Paper 29890457 Paper 29769727 Paper 29548673 Paper 29490164 Paper 29056340 Paper 28806280 Paper 28722709 Paper 28462530 Paper 27828940 Paper 27733577 Paper 27621420 Paper 27455420 Paper 27424290 Paper 27319343 Paper 27286792 Paper 27264187 Paper 27250564 Paper 27027355 Paper 26929373 Paper 26487367 Paper 26085213 Paper 25813085 Paper 25762060 Paper 25646302 Paper 25646268 Paper 25557953 Paper 25344724 Paper 25160819 Paper 25145756 Paper 25083866 Paper 25068121 Paper 24904089 Paper 24903539 Paper 24795727 Paper 24760882 Paper 24636473 Paper 24590763 Paper 24583479 Paper 24576111 Paper 24556406 Paper 24319447 Paper 24252977 Paper 24129162 Paper 24104458 Paper 24072822 Paper 23960190 Paper 23959575 Paper 23945543 Paper 23797094 Paper 23747510 Paper 23695510 Paper 23691015 Paper 23615072 Paper 23501398 Paper 23477737 Paper 23461895 Paper 23429460 Paper 23395676 Paper 23265693 Paper 23256766 Paper 23232296 Paper 22871668 Paper 22729248 Paper 22643351 Paper 22626501 Paper 22528124 Paper 22466933 Paper 22466932 Paper 22460741 Paper 22447352 Paper 22267597 Paper 22197976 Paper 22045567 Paper 22031018 Paper 21951685 Paper 21937703 Paper 21587231 Paper 21438101 Paper 21248151 Paper 21147109 Paper 21074754 Paper 21056041 Paper 20978345 Paper 20958317 Paper 20664576 Paper 20594134 Paper 20137905 Paper 20054607 Paper 19741597 Paper 19733489 Paper 19665769 Paper 19637360 Paper 19592489 Paper 19571798

Abstract

The IFN consensus sequence binding protein (ICSBP/IRF-8), which belongs to the interferon[unreadable] regulatory factor family of transcription factors, is essential for a Thl immune response.[unreadable] ICSBP plays an important role in the host defense against microbial pathogens, but the exact[unreadable] roles of ICSBP in inflammation and chronic inflammatory diseases are still not clear. IL-10-/-[unreadable] mice, which develop colitis characterized by increased Thl cytokines, mimic many aspects of[unreadable] human Crohn's disease (CD). The importance of ICSBP in the development of colitis is shown[unreadable] by the lack of disease in ICSBP and IL-10 double knockout mice. In addition, ICSBP mRNA[unreadable] and protein are highly expressed in the colons of IL-10-/- mice with colitis, while expression[unreadable] of IL-12 and iNOS is significantly compromised in ICSBP/IL-10 double KO mice. In agreement[unreadable] with these results, patients with CD have significantly higher ICSBP expression than normal[unreadable] individuals. ICSBP is active in several loci. ICSBP interacts with TRAF6 in the TLR4 pathway,[unreadable] and binds to ISRE sites in the iNOS and IL-12 p40 promoters, activating the expression of[unreadable] these genes. In addition, we find that ICSBP is ubiquitinated by the E3 ligase Cbl, resulting in[unreadable] its degradation by the proteasome. To expore ICSBP as a suitable target for therapy in CD,[unreadable] this proposal is structured around three aims: 1) We will analyze the regulation of ICSBP[unreadable] expression in macrophages and dendritic cells activated with various TLR and NOD2 ligands.[unreadable] In addition, we will define the role of ICSBP in the generation of regulatory T cells. 2) We will[unreadable] define the function of Cbl in the control of Thl immune immune response and analyze the[unreadable] role of Cbl in the development of colitis. 3) We will define the therapeutic effects of TLR4 and[unreadable] ICSBP inhibition by cell-permeable peptide reagent in vivo in murine colitis models. These[unreadable] studies will advance our understanding the role of ICSBP in the mucosal immune response,[unreadable] and may identify ICSBP as a new target for therapy in CD.

View original record on NIH RePORTER →