Endoplasmic reticulum stress-induced transcription factor, CHOP, is crucial for dendritic cell IL-23 expression.
The endoplasmic reticulum (ER) stress response detects malfunctions in cellular physiology, and microbial pattern recognition receptors recognize external threats posed by infectious agents. This study has investigated whether proinflammatory cytokine expression by monocyte-derived dendritic cells is affected by the induction of ER stress. Activation of ER stress, in combination with Toll-like receptor (TLR) agonists, markedly enhanced expression of mRNA of the unique p19 subunit of IL-23, and also significantly augmented secretion of IL-23 protein. These effects were not seen for IL-12 secretion. The IL-23 gene was found to be a target of the ER stress-induced transcription factor C/EBP homologous protein (CHOP), which exhibited enhanced binding in the context of both ER stress and TLR stimulation. Knockdown of CHOP in U937 cells significantly reduced the synergistic effects of TLR and ER stress on IL-23p19 expression, but did not affect expression of other LPS-responsive genes. The integration of ER stress signals and the requirement for CHOP in the induction of IL-23 responses was also investigated in a physiological setting: infection of myeloid cells with Chlamydia trachomatis resulted in the expression of CHOP mRNA and induced the binding of CHOP to the IL-23 promoter. Furthermore, knockdown of CHOP significantly reduced the expression of IL-23 in response to this intracellular bacterium. Therefore, the effects of pathogens and other environmental factors on ER stress can profoundly affect the nature of innate and adaptive immune responses.
Goodall
Jane C
JC
Department of Medicine, University of Cambridge, School of Clinical Medicine, Addenbrookes Hospital, Cambridge CB2 0QQ, United Kingdom. jcg23@medschl.cam.ac.uk
Wu
Changxin
C
Zhang
Yongsheng
Y
McNeill
Louise
L
Ellis
Lou
L
Saudek
Vladimir
V
Gaston
J S Hill
JS
D045744:Cell Line, Tumor; D002690:Chlamydia Infections / Q000276:immunology; D047369:Chromatin Immunoprecipitation; D003713:Dendritic Cells / Q000276:immunology*; D004721:Endoplasmic Reticulum / Q000276:immunology* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D053759:Interleukin-23 / Q000276:immunology* / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D013312:Stress, Physiological / Q000276:immunology*; D051742:Transcription Factor CHOP / Q000378:metabolism*
D053759:Interleukin-23; D051742:Transcription Factor CHOP