AP-1 Activated by Toll-like Receptors Regulates Expression of IL-23 p19

Liu, Weicheng; Ouyang, Xinshou; Yang, Jianjun; Liu, Jianguo; Liu, Qingshan; Gu, Yongpeng; Fukata, Masayuki; Lin, Tony; He, John Cijiang; Abreu, María T.; Unkeless, Jay C.; Mayer, Lloyd; Xiong, Huabao

doi:10.1074/jbc.m109.025528

Cited by 121 publications

(104 citation statements)

References 43 publications

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“…As a functional correlate, we demonstrated that LPS-induced Il23a and IL-23 expression is in fact increased in NF-B p50 Ϫ/Ϫ BMMs. The Il23a gene is activated through MyD88-dependent and MyD88-independent pathways (18). LPS-induced MAPK (ERK, JNK, and p38) activation has also been shown to regulate Il23a in macrophages (15,18,19).…”

Section: Discussionmentioning

confidence: 99%

“…The Il23a gene is activated through MyD88-dependent and MyD88-independent pathways (18). LPS-induced MAPK (ERK, JNK, and p38) activation has also been shown to regulate Il23a in macrophages (15,18,19). In the RAW 264.7 macrophage cell line, putative SMAD-2-, ATF-2-, IRF-3-, and IRF-7-binding sites were identified through sequence homologies in the Il23a promoter.…”

Section: Discussionmentioning

confidence: 99%

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Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Sheikh

Matsuoka

Onyiah

et al. 2011

Journal of Biological Chemistry

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IL-23 is a heterodimeric cytokine composed of a p19 subunit (Il23a) and a p40 subunit (Il12b) also shared with IL-12. Il23a is expressed in macrophages and dendritic cells and is induced by microbial products such as LPS (1). The importance of IL-23 in the pathogenesis of chronic inflammatory disorders is supported by the recent identification of IL-23 receptor susceptibility alleles associated with the inflammatory bowel diseases, psoriasis, and spondyloartropathies (2). IL-23-driven inflammation has been linked to its role in the development and persistence of a pathogenic subset of Thelper type 17 (T H 17) cells (3).Recently, we demonstrated a protective role for IFN-␥, the signature T H 1 cytokine, in chronic intestinal inflammation through attenuation of Il23a gene expression (4). IFN-␥ receptor deficiency exacerbated IL-23-mediated colitis in IL-10-deficient (IL-10 Ϫ/Ϫ ) mice. Although the molecular regulation of IL-12 p35 (Il12a) and Il12b expression has been well studied, many important questions remain about Il23a regulation in macrophages (1).Toll-like receptors (TLRs) 2 induce Il23a expression in macrophages through recruitment of NF-B family members to binding sites in the proximal promoter (5). We demonstrated that IFN-␥ inhibited LPS-induced NF-B RelA while enhancing p50 subunit recruitment to the Il23a promoter (4). IFN-␥-mediated IL-23 inhibition was in striking contrast to its augmentation of LPS-induced IL-12 p40 and IL-12 p70 expression (4). Notably, TLR and IFN-␥ transcriptional response in the Il12a and Il12b promoters is mediated by interferon regulatory factor (IRF) family members (1). Specifically, mice deficient in IRF-1, IRF-2, and IRF-8 demonstrate defects in Il12a and Il12b production (6). The reciprocal regulation of IL-12 family members by IFN-␥ highlights its complex biological role in the maintenance of immune homeostasis.In these experiments, we functionally characterize an interferon-stimulated response element (ISRE) in the Il23a promoter. This ISRE mediated Il23a promoter induction by LPS and inhibition of LPS-induced activity by IFN-␥. LPS-and IFN-␥-induced IRF-1 is identified as a negative regulator of IL-23 in macrophages and experimental colitis. EXPERIMENTAL PROCEDURES Mice-WT, IL-10Ϫ/Ϫ , NF-B p50 Ϫ/Ϫ , and IRF-1 Ϫ/Ϫ mice on a C57BL/6 background were matched for age in all experiments. IRF-1/IL-10 Ϫ/Ϫ mice were obtained by crossing IL-10 Ϫ/Ϫ and IRF-1 Ϫ/Ϫ mice. Heterozygous offspring were then bred to obtain homozygous IL-10/IRF-1 Ϫ/Ϫ mice. Age-

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Sheikh

Matsuoka

Onyiah

et al. 2011

Journal of Biological Chemistry

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“…HEK-293T cell nuclear extracts were prepared as described previously (48). EMSA probes were prepared by annealing complementary single-stranded oligonucleotides with 5′-GG overhangs (Sigma-Aldrich) and were labeled by filling in with [α-32P] dCTP using the Ready-To-Go kit (GE Healthcare, Amersham).…”

Section: Methodsmentioning

confidence: 99%

Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis

Menon¹,

Chuang²,

Li³

et al. 2014

J. Clin. Invest.

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“…The presence of IL-6 and IL-23 during priming of myelin-specific Th17 cells is essential for triggering EAE (40,41,62,63). Because TLR/ MyD88 signaling activates NF-kB, resulting in IL-23 transcription and subsequently Th17 specification (47), it was likely that SFN controls IL-23 production by altering the NF-kB pathway. According to our assumption, we found suppressed NF-kB reporter activity by SFN without affecting IkB-a degradation.…”

Section: Sfn Treatment Inhibits Il23a/il12b Expression and Th17/th1 Dmentioning

confidence: 99%

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

Geisel

Brück

Glocova

et al. 2014

The Journal of Immunology

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Sulforaphane (SFN), an isothiocyanate, is part of an important group of naturally occurring small molecules with anti-inflammatory properties. The published reports are best conceivable with an inhibition of T cell function, but the mode of action remains unknown. We therefore analyzed the effect of SFN on T cell–mediated autoimmune disease. Feeding mice with SFN protected from severe experimental autoimmune encephalomyelitis. Disease amelioration was associated with reduced IL-17 and IFN-γ expression in draining lymph nodes. In vitro, SFN treatment of T cells did not directly alter T cell cytokine secretion. In contrast, SFN treatment of dendritic cells (DCs) inhibited TLR4-induced IL-12 and IL-23 production, and severely suppressed Th1 and Th17 development of T cells primed by SFN-treated DCs. SFN regulated the activity of the TLR4-induced transcription factor NF-κB, without affecting the degradation of its inhibitor IκB-α. Instead, SFN treatment of DCs resulted in strong expression of the stress response protein heme oxygenase-1 (HO-1), which interacts with and thereby inhibits NF-κB p65. Consistent with these findings, HO-1 bound to p65 and subsequently inhibited the p65 activity at the IL23a and IL12b promoters. Importantly, SFN suppressed Il23a and Il12b expression in vivo and silenced Th17/Th1 responses within the CNS. Thus, our data show that SFN improves Th17/Th1-mediated autoimmune disease by inducing HO-1 and inhibiting NF-κB p65-regulated IL-23 and IL-12 expression.

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AP-1 Activated by Toll-like Receptors Regulates Expression of IL-23 p19

Cited by 121 publications

References 43 publications

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Characterization of an Interferon-stimulated Response Element (ISRE) in the Il23a Promoter

Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis

Sulforaphane Protects from T Cell–Mediated Autoimmune Disease by Inhibition of IL-23 and IL-12 in Dendritic Cells

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