Abstract
Current views on the control of IL-23 production focus on the regulation of il23a, the gene encoding IL-23 p19, by NF-κB in combination with other transcription factors. C/EBP homologous protein (CHOP), X2-Box-binding protein 1 (XBP1), activator protein 1 (AP1), SMAD, CCAAT/enhancer-binding protein (C/EBPβ), and cAMP-response element-binding protein (CREB) have been involved in response to LPS, but no data are available regarding the mechanism triggered by the fungal mimic and β-glucan-containing stimulus zymosan, which produces IL-23 and to a low extent the related cytokine IL-12 p70. Zymosan induced the mobilization of CHOP from the nuclear fractions to phagocytic vesicles. Hypha-forming Candida also induced the nuclear disappearance of CHOP. Assay of transcription factor binding to the il23a promoter showed an increase of Thr(P)-71-Thr(P)-69-activating transcription factor 2 (ATF2) binding in response to zymosan. PKC and PKA/mitogen- and stress-activated kinase inhibitors down-regulated Thr(P)-71-ATF2 binding to the il23a promoter and il23a mRNA expression. Consistent with the current concept of complementary phosphorylations on N-terminal Thr-71 and Thr-69 of ATF2 by ERK and p38 MAPK, MEK, and p38 MAPK inhibitors blunted Thr(P)-69-ATF2 binding. Knockdown of atf2 mRNA with siRNA correlated with inhibition of il23a mRNA, but it did not affect the expression of il12/23b and il10 mRNA. These data indicate the following: (i) zymosan decreases nuclear proapoptotic CHOP, most likely by promoting its accumulation in phagocytic vesicles; (ii) zymosan-induced il23a mRNA expression is best explained through coordinated κB- and ATF2-dependent transcription; and (iii) il23a expression relies on complementary phosphorylation of ATF2 on Thr-69 and Thr-71 dependent on PKC and MAPK activities.
Highlights
Phagocytosis and Th17 immune response control fungal invasion
Because previous studies suggested that C/EBP homologous protein (CHOP) and X2-Box-binding protein 1 (XBP1) are involved in il23a trans-activation, we posited the possible occurrence of the UPR in dendritic cells (DC) stimulated with zymosan
Because phosphatase type 2A (PP2A) can be activated by 1,9-dideoxyforskolin [25], we addressed its effect on XBP1 splicing. ddF inhibited the splicing of XBP1 and the induction of CHOP mRNA produced by tunicamycin but not the effect of zymosan (Fig. 5, A–D)
Summary
Phagocytosis and Th17 immune response control fungal invasion. Results: -Glucans mobilize nuclear C/EBP homologous protein (CHOP) and increase activating transcription factor 2 (ATF2) binding to the il23a promoter. Our results have disclosed the following: (i) a central role for ATF2 in the transcriptional regulation of il23a by zymosan, most likely related to the ability of the -glucan receptor dectin-1 to activate protein kinases A, C, and MAPK; (ii) the disappearance of nuclear CHOP protein during the phagocytosis of zymosan and hypha forming Candida yeast by DC, suggesting that the disappearance of CHOP might be a mechanism to preserve phagocytic cells from the apoptosis associated with CHOP activity during fungal invasion but is not involved in IL-23 production
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