Aberrant innate immune responses in TLR-ligand activated HLA-B27 transgenic rat cells.
BACKGROUND
Commensal enteric microbiota initiate and perpetuate immune-mediated colitis in HLA-B27 transgenic (TG) rats but not wildtype (non-TG) littermates. However, the role of the innate immune response to bacterial components has not been established.


METHODS
We examined responses induced by bacterial adjuvants through Toll-like receptor (TLR) and NOD2 signaling in T-cell-depleted splenocytes from HLA-B27 TG rats versus non-TG controls.


RESULTS
We found that various bacterial adjuvants induced TNF production by cells obtained from specific pathogen-free (SPF) and germ-free (GF, sterile) TG and non-TG rats. Peptidoglycan-polysaccharide (PG-PS), lipopolysaccharide (LPS), and CpG DNA motifs stimulated higher levels of TNF production by SPF TG rat spleen cells compared to non-TG cells. CD11b/c cell depletion eliminated PG-PS and LPS-induced TNF and dramatically reduced CpG-stimulated TNF production. Both SPF and GF TG rat spleens contain more cells that express high levels of CD11b/c and show enhanced mRNA expression of TLR-2 and TLR-4 compared to non-TG rat spleens. In contrast, constitutive and bacterial-induced IL-10 production was markedly lower in TG cells compared to non-TG cells of rats from the same SPF or GF housing conditions. Notably, the ratio of TNF to IL-10 produced after TLR ligand activation was significantly higher in TG than non-TG cells.


CONCLUSIONS
HLA-B27 TG rats have an aberrant cell composition, altered functional TLR expression, and an intrinsic defect in IL-10 production in response to TLR ligands, which may result in exaggerated proinflammatory responses to commensal enteric bacteria and uncontrolled inflammation in this colitis model.
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA.
Bi-Feng
BF
Qian
Susan L
SL
Tonkonogy
R Balfour
RB
Sartor
D000818:Animals; D001419:Bacteria / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D005856:Germ-Free Life / Q000276:immunology*; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D055647:Rats, Transgenic; D013047:Specific Pathogen-Free Organisms / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D051193:Toll-Like Receptors / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015796:HLA-B27 Antigen; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10