Human IBD probably results from a dysregulated mucosal immune response to normal intestinal bacteria. Substance P (SP) is a sensory neuropeptide produced and secreted by nerves and leukocytes in inflammatory bowel disease (IBD). We showed that SP is a Th1-type cytokine that functions through a T cell neurokinin 1 receptor (NK- 1R) to drive Th1 responses. T cell NK-1 R display appears up regulated in human IBD. In IL10-/- mice, piroxicam (a NSAID) induces chronic Th1 colitis and expression of NK-1 Ron gut T cells like seen in human IBD. Our data show that NK-1R inhibitors block ongoing inflammation in this animal model of colitis attesting to the importance of NK-1R in the inflammatory process. Moreover, several Th1-type cytokines (1L12, IL18, TNFalpha) induce T cell NK-1R expression, while others (IL10, TGFalpha) block its display suggesting that this receptor is subject to immune regulation. Thus, our overall hypothesis is that NK-1R, which is the major receptor for SP, is an inducible and highly regulated mucosal T cell receptor that helps drive the aberrant intestinal inflammation of IBD. Using piroxicam-induced IL10-/- colitis, which is an excellent IBD model, this proposal will further investigate these discoveries with three specific aims:
Aim I derives from studies suggesting that SP acts directly on the T cell NK-1R to regulate Th1 responses. Therefore, using various transgenic mice developed in our laboratory, Aim I will explore the hypothesis that the NK-1R induced on T cells is critically important for regulating intestinal Th1 inflammation. Also, we showed that the T cell NK-1 R gene is subject to immune regulation. We postulate, based on preliminary data, that the various cytokines mentioned above primarily affect the NFkappaB pathway of cellular activation to govern T cell NK-1R gene transcription. Thus, using chemical inhibitors, transgenic mice and cells transfected with reporter gene and other vector constructs, Aim II will identify the intracellular signaling pathways that control NK-1R expression in T cells (mucosal, splenic and clones). We also postulate, as suggested by preliminary data, that NK-1R engagement results in receptor internalization and re-distribution, which is another important mechanism of NK-1R control in the mucosa and that cytokines regulate this process.
Aim III will study how inflammatory mediators work to regulate T cell NK-1R cycling and function using T cell clones transfected with various probes and mucosal T cells. Strategies aimed at modulating NK-1 R function in the gut could prove therapeutically beneficial for IBD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK038327-19
Application #
7118511
Study Section
Special Emphasis Panel (ZRG1-GMPB (01))
Program Officer
Hamilton, Frank A
Project Start
1986-04-19
Project End
2010-08-31
Budget Start
2006-09-01
Budget End
2007-08-31
Support Year
19
Fiscal Year
2006
Total Cost
$340,541
Indirect Cost
Name
Tufts University
Department
Type
DUNS #
079532263
City
Boston
State
MA
Country
United States
Zip Code
02111
Elliott, D E; Weinstock, J V (2017) Nematodes and human therapeutic trials for inflammatory disease. Parasite Immunol 39:
Hang, Long; Blum, Arthur M; Kumar, Sangeeta et al. (2016) Downregulation of the Syk Signaling Pathway in Intestinal Dendritic Cells Is Sufficient To Induce Dendritic Cells That Inhibit Colitis. J Immunol 197:2948-57
Weinstock, J V (2015) Substance P and the regulation of inflammation in infections and inflammatory bowel disease. Acta Physiol (Oxf) 213:453-61
Weinstock, Joel V; Elliott, David E (2014) Helminth infections decrease host susceptibility to immune-mediated diseases. J Immunol 193:3239-47
Hang, Long; Blum, Arthur M; Setiawan, Tommy et al. (2013) Heligmosomoides polygyrus bakeri infection activates colonic Foxp3+ T cells enhancing their capacity to prevent colitis. J Immunol 191:1927-34
Leung, John; Hang, Long; Blum, Arthur et al. (2012) Heligmosomoides polygyrus abrogates antigen-specific gut injury in a murine model of inflammatory bowel disease. Inflamm Bowel Dis 18:1447-55
Blum, Arthur M; Hang, Long; Setiawan, Tommy et al. (2012) Heligmosomoides polygyrus bakeri induces tolerogenic dendritic cells that block colitis and prevent antigen-specific gut T cell responses. J Immunol 189:2512-20
Elliott, David E; Weinstock, Joel V (2012) Helminth-host immunological interactions: prevention and control of immune-mediated diseases. Ann N Y Acad Sci 1247:83-96
Walk, Seth T; Blum, Arthur M; Ewing, Sarah Ang-Sheng et al. (2010) Alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus. Inflamm Bowel Dis 16:1841-9
Beinborn, Martin; Blum, Arthur; Hang, Long et al. (2010) TGF-beta regulates T-cell neurokinin-1 receptor internalization and function. Proc Natl Acad Sci U S A 107:4293-8

Showing the most recent 10 out of 52 publications