The investigators propose to define the molecular mechanisms of T-cell activation and TH-1 cytokine secretion in lamina propria T-cells induced by the antigen-independent CD2 pathway. The nuclear events responsible for TH-1 cytokine gene expression will be examined. Data from the investigator s laboratory have shown a predominance of the CD2 activation pathway, maximized by CD28 coligation, in TCR independent stimulation of TH-1 cytokine secretion from normal lamina propria T-cells. Their analysis of Crohn s disease patients following treatment with anti-TNFalpha monoclonal antibodies demonstrated that mucosal T-cells in vitro become unresponsive to CD2 and CD28 signaling in clinical response of patients. Their research has shown that activated B-cells in the intestinal mucosal are different than activated peripheral blood T-cells. A byproduct of these studies has been the development of a model to study mucosal T-cell regulation. The model, using T-cell activated peripheral blood T-cells, reproduces the functional and biochemical activation state of mucosal T-cells and is a model for investigation of CD2 regulation of mucosal T-cell cytokine genes. Molecular analysis has shown that CD2, but not CD3, ligation of LP-like T-cells is followed by a marked increase in cytokine mRNA production. This response is preceded by induction of AP-1 composed of jun/fos heterodimers. Western blot studies show expression of fos following CD2 ligation. The investigators will use the LP-like T-cell as a system for examination of the hypothesis that induction and/or modification of AP-1 or protein expression with binding of AP-1 and/or NAFT to DNA sequence in their respective promoter regions is central to both IL-1 and interferon-gamma gene expression in lamina propria T-cells following CD2 pathway activation.
Their aims are to understand CD2 and/or CD28 regulation of IL-2 and interferon-gamma gene expression in lamina propria T-cells by determining: 1). Whether the augmented IL-2 and interferon-( production seen in lamina propria-like and lamina propria T-cells following CD2 and/or CD28 ligation occurs by increased transcriptional activation and/or mRNA stability. 2). Identifying cis-acting regulatory regions within the IL-2 and interferon-( promotor regions that affect gene transcription following activation of the CD2 and CD28 pathways. 3). The constitutive composition of the jun and jun/fos AP-1 in LP-like and LPT cells and whether activation by CD2 and/or CD28 results in differences in the expression in composition of these dimeric proteins.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK043211-07
Application #
2634226
Study Section
General Medicine A Subcommittee 2 (GMA)
Program Officer
Hamilton, Frank A
Project Start
1991-09-20
Project End
2000-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Cedars-Sinai Medical Center
Department
Type
DUNS #
075307785
City
Los Angeles
State
CA
Country
United States
Zip Code
90048
Gonsky, Rivkah; Fleshner, Phillip; Deem, Richard L et al. (2017) Association of Ribonuclease T2 Gene Polymorphisms With Decreased Expression and Clinical Characteristics of Severity in Crohn's Disease. Gastroenterology 153:219-232
Gonsky, Rivkah; Deem, Richard L; Landers, Carol J et al. (2014) IFNG rs1861494 polymorphism is associated with IBD disease severity and functional changes in both IFNG methylation and protein secretion. Inflamm Bowel Dis 20:1794-801
Gonsky, Rivkah; Deem, Richard L; Targan, Stephan R (2013) Multiple activating and repressive cis-promoter regions regulate TNFSF15 expression in human primary mononuclear cells. Cytokine 63:36-42
Gonsky, Rivkah; Deem, Richard L; Landers, Carol J et al. (2011) Distinct IFNG methylation in a subset of ulcerative colitis patients based on reactivity to microbial antigens. Inflamm Bowel Dis 17:171-8
Gonsky, Rivkah; Deem, Richard L; Targan, Stephan R (2009) Distinct Methylation of IFNG in the Gut. J Interferon Cytokine Res 29:407-14
Cohavy, Offer; Targan, Stephan R (2007) CD56 marks an effector T cell subset in the human intestine. J Immunol 178:5524-32
Gonsky, R; Deem, R L; Bream, J H et al. (2006) An IFNG SNP with an estrogen-like response element selectively enhances promoter expression in peripheral but not lamina propria T cells. Genes Immun 7:342-51
Cohavy, Offer; Zhou, Jaclyn; Ware, Carl F et al. (2005) LIGHT is constitutively expressed on T and NK cells in the human gut and can be induced by CD2-mediated signaling. J Immunol 174:646-53
Bream, Jay H; Hodge, Deborah L; Gonsky, Rivkah et al. (2004) A distal region in the interferon-gamma gene is a site of epigenetic remodeling and transcriptional regulation by interleukin-2. J Biol Chem 279:41249-57
Prehn, John L; Mehdizadeh, Shahab; Landers, Carol J et al. (2004) Potential role for TL1A, the new TNF-family member and potent costimulator of IFN-gamma, in mucosal inflammation. Clin Immunol 112:66-77

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