Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function

Andrea La Sala, Jianping He, Leopoldo Laricchia-Robbio, Stefania Gorini, Akiko Iwasaki, Michael Braun, George S. Yap, Alan Sher, Keiko Ozato, Brian Kelsall

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Pages (from-to)1227-1235
Number of pages9
JournalJournal of Experimental Medicine
Volume206
Issue number6
DOIs
Publication statusPublished - Jun 8 2009

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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    La Sala, A., He, J., Laricchia-Robbio, L., Gorini, S., Iwasaki, A., Braun, M., Yap, G. S., Sher, A., Ozato, K., & Kelsall, B. (2009). Cholera toxin inhibits IL-12 production and CD8α+ dendritic cell differentiation by cAMP-mediated inhibition of IRF8 function. Journal of Experimental Medicine, 206(6), 1227-1235. https://doi.org/10.1084/jem.20080912