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.
Qian
Bi-Feng
BF
Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, NC 27599, USA.
Tonkonogy
Susan L
SL
Sartor
R Balfour
RB
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