Reduced responsiveness of HLA-B27 transgenic rat cells to TGF-beta and IL-10-mediated regulation of IFN-gamma production.
BACKGROUND
We have reported that commensal luminal bacterial components induce an active in vitro IFN-gamma response in mesenteric lymph node (MLN) and intestinal cells from specific pathogen-free (SPF) HLA-B27 transgenic (TG) rats with chronic colitis but not in cells from non-diseased SPF non-TG, germ-free (GF) non-TG or GF TG rats.


METHODS
The study examined IL-12 stimulation of MLN IFN-gamma responses to luminal bacteria and regulation of these responses by suppressive cytokines.


RESULTS
Exogenous IL-12 significantly increased the bacterial lysate-induced IFN-gamma response in SPF TG MLN cells, while bacterial lysate and IL-12 synergistically induced IFN-gamma from low baseline levels in cells obtained from both SPF and GF non-TG rats, and in GF TG cells. TGF-beta fully counteracted the effects of IL-12 and bacterial lysate on non-TG cells by almost completely inhibiting IFN-gamma production. In contrast, TG cells were less responsive to TGF-beta-mediated downregulation with a substantial residual IFN-gamma response to IL-12 plus bacterial lysate. Further experiments showed that CD4+/CD25+ cells had no inhibitory effect on the IFN-gamma production and were not required for TGF-beta-mediated suppression. Addition of exogenous IL-10 also partially inhibited IFN-gamma production by non-TG cells but did not affect TG cells. Conversely, exogenous IL-12 preferentially suppressed bacterial lysate-induced TGF-beta and IL-10 production in TG rat cells.


CONCLUSIONS
An attenuated response to regulatory signals leads to uncontrolled potentiated induction of effector IFN-gamma responses to commensal bacteria in HLA-B27 TG rats that spontaneously develop chronic intestinal inflammation.
Qian
Bi-Feng
BF
Center for Gastrointestinal Biology and Disease, Department of Medicine, University of North Carolina, Chapel Hill, North Carolina 27599, USA.
Tonkonogy
Susan L
SL
Sartor
R Balfour
RB
D000818:Animals; D030801:Animals, Genetically Modified; D001419:Bacteria / Q000276:immunology; D015153:Blotting, Western; D002478:Cells, Cultured; D003092:Colitis / Q000503:physiopathology; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D015796:HLA-B27 Antigen / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis*; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D008198:Lymph Nodes / Q000187:drug effects; D008643:Mesentery; D051381:Rats; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D015796:HLA-B27 Antigen; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma