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

Figure 2

Interactions of downstream pathways of IRE1α for the transcriptional regulation of IL-1β and TNF-α in response to ER stress. ER stress-induced IRE1α activation differentially regulates IL-1β and TNF-α through GSK-3β activation and XBP1 splicing, respectively. IRE1α-mediated GSK-3β activation induces transcription of IL-1β but inhibits XBP1 splicing. Thus, SB216763, a GSK-3β inhibitor, selectively inhibits IL-1β gene expression and increases TNF-α production in response to ER stress. In contrast, IRE1α-mediated XBP1 activation results in the transcription of TNF-α. STF083010, IRE1α RNase inhibitor, suppresses TNF-α production without affecting IL-1β production. In addition, activation of XBP1 by ER stress inducers synergistically augments LPS-mediated TNF-α production. Likewise, GSK-β activation by ER stress inducer augments LPS-mediated IL-1β.