CD40L-induced IL-12 production is further enhanced by the Th2 cytokines IL-4 and IL-13.
Interaction of the CD40L (CD154) molecule on activated T cells with its receptor, CD40, on macrophages and dendritic cells (DC) provides a strong signal for interleukin (IL)-12 production. As IL-12 is the most important factor in driving Th precursor (Thp) cells into T(h)elper 1 cells, CD40-CD40L interactions strongly promote Th1 differentiation. Th2 cytokines (IL-4, IL-13, IL-10) on the other hand, are known to inhibit Th1 differentiation, and to promote either directly or indirectly, Th2 differentiation. Inhibition of lipopolysaccharide (LPS)-induced IL-12 production by IL-4, IL-13 and IL-10 is supposed to be one such mechanism. However, we here report that IL-4 and IL-13 enhance p70 IL-12 production and p40 mRNA transcription by human monocytes when the latter are stimulated trough triggering of CD40. This effect on IL-12 induction is most clear in the presence of interferon (IFN)-gamma, which upregulates CD40 expression. IL-10 potently inhibits IL-12 production. The increased IL-12 production in the presence of IL-4 and IL-13 is however, not the indirect result of a reduction in IL-10 production, but is most likely owing to a direct effect of IL-4 and IL-13. We conclude that IL-4 and IL-13 enhance rather than decrease the IL-12 production by human monocytes during interaction with T cells. This effect can potentially contribute in vivo to switching of an ongoing Th2 response towards a Th1 response and the findings also support the dominant effect of CD40/CD40L interaction on Th1 development, even in the presence of Th2 cytokines.
Bullens
D M
DM
Laboratory of Experimental Immunology, Department of Pathophysiology, Faculty of Medicine, Catholic University of Leuven (KUL), Leuven, Belgium.
Kasran
A
A
Thielemans
K
K
Bakkus
M
M
Ceuppens
J L
JL
D019898:Autocrine Communication; D001402:B-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D006801:Humans; D016753:Interleukin-10 / Q000276:immunology; D018664:Interleukin-12 / Q000096:biosynthesis* / Q000235:genetics; D018793:Interleukin-13 / Q000494:pharmacology*; D015847:Interleukin-4 / Q000494:pharmacology*; D008297:Male; D009000:Monocytes / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D018418:Th2 Cells / Q000276:immunology*; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation
D018793:Interleukin-13; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12; D015847:Interleukin-4