期刊
JOURNAL OF IMMUNOLOGY
卷 178, 期 8, 页码 4811-4819出版社
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.178.8.4811
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资金
- NIDCR NIH HHS [DE06746, DE13833, DE015254, DE017138] Funding Source: Medline
- Wellcome Trust Funding Source: Medline
The type IIb heat-labile enterotoxin of Escherichia coli (LT-IIb) and its nontoxic pentameric B subunit (LT-IIb-B-5) display different immunomodulatory activities, the mechanisms of which are poorly understood. We investigated mechanisms whereby the absence of the catalytically active A subunit from LT-IIb-B-5 renders this molecule immunostimulatory through TLR2. LT-IIb-B-5, but not LT-IIb, induced TLR2-mediated NF-kappa B activation and TNF-alpha production. These LT-IIb-B-5 activities were antagonized by LT-IIb; however, inhibitors of adenylate cyclase or protein kinase A reversed this antagonism. The LT-IIb antagonistic effect is thus likely dependent upon the catalytic activity of its A subunit, which causes elevation of intracellular cAMP and activates cAMP-dependent protein kinase A. Consistent with this, a membrane-permeable cAMP analog and a cAMP-elevating agonist, but not catalytically defective point mutants of LT-IIb, mimicked the antagonistic action of wild-type LT-IIb. The mutants moreover displayed increased proinflammatory activity compared with wild-type LT-IIb. Additional mechanisms for the divergent effects on TLR2 activation by LT-IIb and LT-IIb-B, were suggested by findings that the latter was significantly stronger in inducing lipid raft recruitment of TLR2 and interacting with this receptor. The selective use of TLR2 by LT-IIb-B, was confirmed in an assay for IL-10, which is inducible by both LT-IIb and LT-IIb-B-5 at comparable levels; TLR2-deficient macrophages failed to induce IL-10 in response to LT-IIb-B-5 but not in response to LT-IIb. These differential immunomodulatory effects by LT-IIb and LT-IIb-B-5 have important implications for adjuvant development and, furthermore, suggest that enterotoxic E. coli may suppress TLR-mediated innate immunity through the action of the enterotoxin A subunit.
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