Differential Regulation of Toll-Like Receptor-Mediated Cytokine Production by Unfolded Protein Response

Figure 1

Interactions of ER stress proteins and cell surface TLR signaling pathways. Phosphorylated IRE1α interacts via TRAF2 with IKK complex and with ASK and JNK. Thus, IRE1α can activate NF-kappaB and AP-1. On the other hand, TLRs stimulate IRE1α-mediated splicing of XBP1 mRNA encoding various cytokines including TNF-α and IL-6. In addition, PERK-mediated translational inhibition leads to a shutdown of de novo synthesis of IκB and thus leads to the activation of NF-kappaB. PERK and ATF6 induce ERK, p38 and JNK activation, resulting in increased expression of IL-6 and IL-8. ATF6 also activates NF-kappaB via phosphorylation of the Akt. ATF4 is involved in the expression of type I interferon and that of IL-23 via activation of GADD34 and CHOP, respectively. TLR4 tightly controls the ATF4-CHOP branch and prevents the induction of CHOP expression in macrophages via activating TRIF.