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Cholera toxin inhibits IL-12 production and CD8⁺ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function

¹ Laboratory of Molecular and Cellular Immunology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, 00163 Rome, Italy
² Mucosal Immunobiology Section, Laboratory of Molecular Immunology, ³ Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Disease, ⁴ Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892
⁵ Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520
⁶ Department of Pediatrics, Division of Pediatric Nephrology and Hypertension, University of Texas Health Science Center–Houston, Houston, TX 77030
⁷ Center for Immunity and Inflammation, University of Medicine and Dentistry of New Jersey Medical School, Newark, NJ 07101

CORRESPONDENCE Brian Kelsall: kelsall{at}nih.gov

Prior studies have demonstrated that cholera toxin (CT) and other cAMP-inducing factors inhibit interleukin (IL)-12 production from monocytes and dendritic cells (DCs). We show that CT inhibits Th1 responses in vivo in mice infected with Toxoplasma gondii. This correlated with low serum IL-12 levels and a selective reduction in the numbers of CD8⁺ conventional DCs (cDCs) in lymphoid organs. CT inhibited the function of interferon (IFN) regulatory factor (IRF) 8, a transcription factor known to positively regulate IL-12p35 and p40 gene expression, and the differentiation of CD8⁺ and plasmacytoid DCs (pDCs). Fluorescence recovery after photobleaching analysis showed that exposure to CT, forskolin, or dibutyryl (db) cAMP blocked LPS and IFN-–induced IRF8 binding to chromatin. Moreover, CT and dbcAMP inhibited the binding of IRF8 to the IFN-stimulated response element (ISRE)–like element in the mouse IL-12p40 promoter, likely by blocking the formation of ISRE-binding IRF1–IRF8 heterocomplexes. Furthermore, CT inhibited the differentiation of pDCs from fms-like tyrosine kinase 3 ligand–treated bone marrow cells in vitro. Therefore, because IRF8 is essential for IL-12 production and the differentiation of CD8⁺ cDCs and pDCs, these data suggest that CT and other Gs-protein agonists can affect IL-12 production and DC differentiation via a common mechanism involving IRF8.

Abbreviations used: cDC, conventional DC; CT, cholera toxin; CTA, CT A subunit; CTB, CT B subunit; FLT-3L, fms-related tyrosine kinase ligand; FRAP, fluorescence recovery after photobleaching; IRF, IFN regulatory factor; ISRE, IFN-stimulated response element; pDC, plasmacytoid DC; TLR, Toll-like receptor.

© 2009 la Sala et al.
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