Systemic Toll-like receptor ligands modify B-cell responses in human inflammatory bowel disease.
BACKGROUND
Bacteria have a central, although poorly understood, role in inflammatory bowel disease (IBD). Host-bacteria interactions primarily take place in the gastrointestinal tract, but cells may also encounter translocated bacteria in the bloodstream. IBD is associated with activated, circulating Toll-like receptor (TLR)2 and TLR4-expressing B cells suggesting that blood-borne microbial TLR ligands modulate B cell responses.


METHODS
Serum levels of lipopolysaccharide (LPS)/endotoxin and high mobility group box 1 (HMGB1), an endogenous TLR ligand, were quantified in Crohn's disease (CD) and ulcerative colitis (UC). Responses of purified B cells to LPS and HMGB1 were correlated with levels of systemic TLR ligands and clinical parameters of disease.


RESULTS
While IBD patients have increased levels of blood LPS, the net effect of endotoxemia has unexpected characteristics illustrating that LPS has both pro- and antiinflammatory roles through TLR4+ B cells. Experimental treatment of B cells demonstrates that the antiinflammatory effect of LPS is due to its hypo-acylation of lipid A suggesting an increased prevalence of systemic, hypo-acylated LPS in CD. In contrast, high levels of LPS are associated with disease activity in UC. HMGB1 activates B cells through TLR2 and CD36. Serum levels of HMGB1 correlate with spontaneous IL-8 production by B cells suggesting that blood-borne TLR2 ligands increase B-cell activation in vivo.


CONCLUSIONS
Systemic TLR ligands modulate B cells towards either proinflammatory or antiinflammatory activity depending on the predominant ligand(s). Further, the circulating B cell may represent an important proxy for quantifying the LPS lipid A acylation burden in patients with IBD.
McDonnell
Marie
M
Section of Endocrinology, Evans Biomedical Research Center, Boston Medical Center, Boston, Massachusetts 02118, USA.
Liang
Yanmei
Y
Noronha
Ansu
A
Coukos
Jennifer
J
Kasper
Dennis L
DL
Farraye
Francis A
FA
Ganley-Leal
Lisa M
LM
D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D003093:Colitis, Ulcerative / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D024243:HMGB1 Protein / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects; D051193:Toll-Like Receptors / Q000276:immunology / Q000378:metabolism*
D016207:Cytokines; D024243:HMGB1 Protein; D008024:Ligands; D008070:Lipopolysaccharides; D051193:Toll-Like Receptors