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TLR Cross-Talk Specifically Regulates Cytokine Production by B Cells from Chronic Inflammatory Disease Patients¹

Madhumita Jagannathan,^* Hatice Hasturk, YanMei Liang, Hyunjin Shin, Jeremy T. Hetzel,^¶ Alpdogan Kantarci, Daniel Rubin,^¶ Marie E. McDonnell,^¶ Thomas E. Van Dyke, Lisa M. Ganley-Leal,² and Barbara S. Nikolajczyk²³

^*Department of Pathology, Boston University School of Medicine, Boston, MA 02118; Department of Periodontology and Oral Biology, Boston University Goldman School of Dental Medicine, Boston, MA 02118; Department of Medicine, Section of Infectious Diseases, Evans Biomedical Research Center, Boston Medical Center, Boston, MA 02118; Department of Microbiology, Boston University School of Medicine, Boston, MA 02118; ^¶Department of Medicine, Section of Endocrinology, Boston Medical Center, Boston, MA 02118

Chronic systemic inflammation links periodontal disease and diabetes to increased incidence of serious comorbidities. Activation of TLRs, particularly TLR2 and TLR4, promotes chronic systemic inflammation. Human B cells have been generally thought to lack these TLRs. However, recent work showed that an increased percentage of circulating B cells from inflammatory disease patients express TLR2 and TLR4, and that TLR engagement on B cells resulted in unexpected changes in gene expression. New data show that B cells from inflammatory disease patients secrete multiple cytokines in response to different classes of TLR ligands. Furthermore, the B cell response to combinations of TLR ligands is cytokine- and ligand-specific. Some cytokines (IL-1β and IL-10) are predominantly regulated by TLR4, but others (IL-8 and TNF-) are predominantly regulated by TLR2, due in part to TLR-dictated changes in transcription factor/promoter association. TLR2 and TLR9 also regulate B cell TLR4 expression, demonstrating that TLR cross-talk controls B cell responses at multiple levels. Parallel examination of B cells from periodontal disease and diabetes patients suggested that outcomes of TLR cross-talk are influenced by disease pathology. We conclude that disease-associated alteration of B cell TLR responses specifically regulates cytokine production and may influence chronic inflammation.

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 in part by National Institutes of Health Grant AI54611 and a Research Grant from the American Diabetes Association (to B.N.); by the Evans Medical Foundation, Broad Medical Research Program of The Broad Foundation, and a Becton Dickinson Grant Award 2007 (to L.M.G.); by U.S. Public Health Service Grants DE018917 (to H.H.) and by National Institutes of Health Grants P50 DE16191 and RR00533 (to T.V.D.).

² L.M.G.-L. and B.S.N. contributed equally to this work.

³ Address correspondence and reprint requests to Dr. Barbara Nikolajczyk, Boston University School of Medicine, Department of Microbiology, 72 East Concord Street, L-516, Boston, MA 02118. E-mail address: bnikol{at}bu.edu

⁴ Abbreviations used in this paper: PD, periodontal disease; ChIP, chromatin immunoprecipitation; DM, diabetes.

⁵ The online version of this article contains supplemental material.