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 CD8α + 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 CD8α + and plasmacytoid DCs (pDCs). Fluorescence recovery after photobleaching analysis showed that exposure to CT, forskolin, or dibutyryl (db) cAMP blocked LPS and IFN-γ–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 CD8α + 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. Footnotes 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. Submitted: 25 April 2008 Accepted: 4 May 2009
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Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function
la Sala, Andrea; He, Jianping; Laricchia-Robbio, Leopoldo; Gorini, Stefania; Iwasaki, Akiko; Braun, Michael; Yap, George S.; Sher, Alan; Ozato, Keiko; Kelsall, Brian
Follow The Journal of Experimental Medicine
, Volume 206 (6): 1227
Rockefeller University Press – Jun 8, 2009
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