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The A Subunit of Type IIb Enterotoxin (LT-IIb) Suppresses the Proinflammatory Potential of the B Subunit and Its Ability to Recruit and Interact with TLR2¹

Shuang Liang^*, Min Wang^*, Kathy Triantafilou, Martha Triantafilou, Hesham F. Nawar, Michael W. Russell, Terry D. Connell and George Hajishengallis^2,*,

^* Center for Oral Health and Systemic Disease, Department of Periodontics, and Department of Microbiology and Immunology, University of Louisville Health Sciences Center, Louisville, KY 40292; Infection and Immunity Group, School of Life Sciences, University of Sussex, Falmer, Brighton, United Kingdom; and Department of Microbiology and Immunology, Witebsky Center for Microbial Pathogenesis and Immunology, State University of New York, Buffalo, NY 14214

The type IIb heat-labile enterotoxin of Escherichia coli (LT-IIb) and its nontoxic pentameric B subunit (LT-IIb-B₅) 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-B₅ renders this molecule immunostimulatory through TLR2. LT-IIb-B₅, but not LT-IIb, induced TLR2-mediated NF-B activation and TNF- production. These LT-IIb-B₅ 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-B₅ 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-B₅ was confirmed in an assay for IL-10, which is inducible by both LT-IIb and LT-IIb-B₅ at comparable levels; TLR2-deficient macrophages failed to induce IL-10 in response to LT-IIb-B₅ but not in response to LT-IIb. These differential immunomodulatory effects by LT-IIb and LT-IIb-B₅ 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by U.S. Public Health Service Grants DE06746 (to M.W.R.), DE13833 (to T.D.C.), and DE015254 and DE017138 (to G.H.) from the National Institutes of Health, and by the Wellcome Trust and the Heart Research Fund (to K.T.).

² Address correspondence and reprint requests to Dr. George Hajishengallis, Department of Microbiology and Immunology, University of Louisville Health Sciences Center, 501 South Preston Street, Room 206, Louisville, KY 40292. E-mail address: g0haji01{at}louisville.edu

³ Abbreviations used in this paper: PKA, protein kinase A; MCD, methyl--cyclodextrin; HEK, human embryonic kidney; CHO, Chinese hamster ovary; FRET, fluorescence resonance energy transfer.

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