Expression levels of cellular inhibitor of apoptosis proteins and colitogenic cytokines are inversely correlated with the activation of interferon regulatory factor 4.

Publisher: Oxford University Press Country of Publication: England NLM ID: 0057202 Publication Model: Print Cited Medium: Internet ISSN: 1365-2249 (Electronic) Linking ISSN: 00099104 NLM ISO Abbreviation: Clin Exp Immunol Subsets: MEDLINE

Publication: 2022- : Oxford : Oxford University Press
Original Publication: Oxford : Blackwell Scientific Publications

Cytokines*/metabolism ; Inhibitor of Apoptosis Proteins*/genetics ; Inhibitor of Apoptosis Proteins*/metabolism ; Inhibitor of Apoptosis Proteins*/pharmacology; Interferon Regulatory Factors/*metabolism; Animals ; Apoptosis ; Humans ; Interferon Regulatory Factors/genetics ; Ligands ; Mice ; Tumor Necrosis Factor-alpha/metabolism

Cellular inhibitors of apoptosis proteins 1 (cIAP1) and 2 (cIAP2) are involved in signaling pathways mediated by Toll-like receptors (TLRs) and tumor necrosis factor (TNF)-α. Excessive activation of TLRs and TNF-α underlies the immunopathogenesis of Crohn's disease (CD) and ulcerative colitis (UC). However, the roles played by cIAP1 and cIAP2 in the development of CD and UC remain poorly understood. In this study, we attempted to clarify the molecular link between cIAP1/cIAP2 and colonic inflammation. Human monocyte-derived dendritic cells (DCs) treated with siRNAs specific for cIAP1 or cIAP2 exhibited reduced pro-inflammatory cytokine responses upon stimulation with TLR ligands. Expression of cIAP1 and cIAP2 in human DCs was suppressed in the presence of interferon regulatory factor 4 (IRF4). This effect was associated with inhibition of cIAP1 and cIAP2 polyubiquitination. To verify these in vitro findings, we created mice overexpressing IRF4 in DCs and showed that these mice were resistant to trinitrobenzene sulfonic acid-induced colitis as compared with wild-type mice; these effects were accompanied by reduced expression levels of cIAP1 and cIAP2. Pro-inflammatory cytokine production by mesenteric lymph node cells upon stimulation with TLR ligands was reduced in mice with DC-specific IRF4 overexpression as compared with that in wild-type mice. Finally, in clinical samples of the colonic mucosa from patients with CD, there was a negative relationship between the percentage of IRF4+ DCs and percentages of cIAP1+ or cIAP2+ lamina propria mononuclear cells. These data suggest that the colitogenic roles of cIAP1 and cIAP2 are negatively regulated by IRF4.
(© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Immunology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

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Keywords: Toll-like receptor; cellular inhibitor of apoptosis protein 1; cellular inhibitor of apoptosis protein 2; colitis; interferon regulatory factor 4

0 (Cytokines)
0 (Inhibitor of Apoptosis Proteins)
0 (Interferon Regulatory Factors)
0 (Ligands)
0 (Tumor Necrosis Factor-alpha)
0 (interferon regulatory factor-4)

Date Created: 20220513 Date Completed: 20220517 Latest Revision: 20230118

20231215

PMC9113101

10.1093/cei/uxac005

35553628