Rodríguez M, Domingo E, Alonso S, Frade JG, Eiros J, Crespo MS, Fernández N
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. CHOP, XBP1, AP1, SMAD, C/EBPβ, and CREB have been involved in response to LPS, but no data are available as to 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 P-Thr71-P-Thr69-ATF2 binding in response to zymosan. PKC and PKA/mitogen- and stress-activated kinase inhibitors down-regulated P-Thr71-ATF2 binding to the il23a promoter and il23a mRNA expression. Consistent with the current concept of complementary phosphorylations on N-terminal Thr71 and Thr69 of ATF2 by ERK and p38 MAPK, MEK, and p38 MAPK inhibitors blunted P-Thr69-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 that: 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. iii) il23a expression relies on complementary phosphorylation of ATF2 on Thr69 and Thr71 dependent on PKC and MAPK activities.