Interleukin‐17 and its target genes: mechanisms of interleukin‐17 function in disease

Onishi, Reiko; Gaffen, Sarah L.

doi:10.1111/j.1365-2567.2009.03240.x

Cited by 784 publications

(658 citation statements)

References 131 publications

(161 reference statements)

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“…High levels of IL-17A are found in IBD; it is secreted by T h 17 cells, CD8 ? T cells, natural killer cells and neutrophils and acts on both immune and nonimmune cells inducing a number of cytokines, chemokines, inflammatory effector molecules and antimicrobial proteins (Onishi and Gaffen 2010). Other genes of this cluster known to be overexpressed in IBD were the chemokines CXCL9 and CXCL11 (Egesten et al 2007;Singh et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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Significant health benefits have been demonstrated for certain probiotic strains through intervention studies; however, there is a shortage of experimental evidence relative to the mechanisms of action. Here, noninvasive experimental procedure based on a colon organ culture system has been used that, in contrast to most experimental in vitro models reported, can preserve natural immunohistochemical features of the human mucosa. This system has been used to test whether commensal lactobacilli (Lactobacillus paracasei BL23, Lactobacillus plantarum 299v and L. plantarum 299v (A -)) were able to hinder inflammation-like signals induced by phorbol 12-myristate 13-acetate (PMA)/ionomycin (IO). Whole genome microarrays have been applied to analyze expression differences, from which mRNA markers could be inferred to monitor the effect of putative probiotic strains under such conditions. Regarding the gene expression, PMA/IO treatment induced not only interleukin (IL)-2 and interferon gamma (IFN-c), as expected, but also other relevant genes related to immune response and inflammation, such as IL-17A, chemokine (C-X-C motif) ligand (CXCL) 9 and CXCL11. The ex vivo culturing did not modify the pattern of expression of those genes or others related to inflammation. Interestingly, this study demonstrated that lactobacilli downregulated those genes and triggered a global change of the transcriptional profile that indicated a clear homeostasis restoring effect and a decrease in signals produced by activated T cells.

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Section: Discussionmentioning

confidence: 99%

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

et al. 2012

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“…In contrast, molecular regulation mediated by IL-17 has been relatively well characterized (7,28,29). IL-17 is known to be a potent mediator of proinflammatory cytokines, chemokines, acute phase response elements, and defensins (7,14,30). IL-17 is associated with the pathophysiology of autoimmune diseases, including RA, IBD, systemic lupus, psoriasis, and autoimmune encephalitis (reviewed in Ref.…”

Section: Discussionmentioning

confidence: 99%

“…IL-17 is associated with the pathophysiology of autoimmune diseases, including RA, IBD, systemic lupus, psoriasis, and autoimmune encephalitis (reviewed in Ref. 30). Recently, this cytokine was also shown to be expressed in atherosclerotic plaques (31).…”

Section: Discussionmentioning

confidence: 99%

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

Turner-Brannen

Choi

Arsenault³

et al. 2011

The Journal of Immunology

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Cytokines IL-32 and IL-17 are emerging as critical players in the pathophysiology of immune-mediated chronic inflammatory diseases. It has been speculated that the molecular mechanisms governing IL-32– and IL-17–mediated cellular responses are differentially dependent on the TNF pathway. In this study, kinome analysis demonstrated that following stimulation with cytokine IL-32, but not IL-17, there was increased phosphorylation of a peptide target corresponding to TNF-R1. Consistent with this observation, blocking TNF-R1 resulted in a suppression of IL-32–induced downstream responses, indicating that IL-32–mediated activity may be dependent on TNF-R1. In contrast, blocking TNF-R1 did not affect IL-17–induced downstream responses. Kinome analysis also implicated p300 (transcriptional coactivator) and death-associated protein kinase-1 (DAPK-1) as signaling intermediates for both IL-32 and IL-17. Phosphorylation of p300 and DAPK-1 upon stimulation with either IL-32 or IL-17 was confirmed by immunoblots. The presence of common targets was supported by results demonstrating similar downstream responses induced in the presence of IL-32 and IL-17, such as transcriptional responses and the direct activation of NF-κB. Furthermore, knockdown of p300 and DAPK-1 altered downstream responses induced by IL-32 and IL-17, and impacted certain cellular responses induced by TNF-α and IL-1β. We hypothesize that p300 and DAPK-1 represent nodes where the inflammatory networks of IL-32 and IL-17 overlap, and that these proteins would affect both TNF-R1–dependent and –independent pathways. Therefore, p300 and DAPK-1 are viable potential therapeutic targets for chronic inflammatory diseases.

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“…To increase macrophage accumulation during PbNK infection, generation and/or recruitment of macrophages must be enhanced. IL-17 is reported to induce production of GM-CSF and CCL2 and CCL7 chemokines [30][31][32]. The former chemokine stimulates progenitor cells to proliferate and differentiate into granulocytes and macrophages, while the latter attracts macrophages to the expression site.…”

Section: Macrophages Recruitment In Response To Macrophagederived Il-mentioning

confidence: 99%

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

et al. 2013

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Although IL-12 is believed to contribute to protective immune responses, the role played by IL-23 (a member of the IL-12 family) in malaria is elusive. Here, we show that IL-23 is produced during infection with Plasmodium berghei NK65. Mice deficient in IL-23 (p19KO) had higher parasitemia and died earlier than wild-type (WT) controls. Interestingly, p19KO mice had lower numbers of IL-17-producing splenic cells than their WT counterparts. Furthermore, mice deficient in IL-17 (17KO) suffered higher parasitemia than the WT controls, indicating that IL-23-mediated protection is dependent on induction of IL-17 during infection. We found that macrophages were responsible for IL-17 production in response to IL-23. We observed a striking reduction in splenic macrophages in the p19KO and 17KO mice, both of which became highly susceptible to infection. Thus, IL-17 appears to be crucial for maintenance of splenic macrophages. Adoptive transfer of macrophages into macrophage-depleted mice confirmed that macrophage-derived IL-17 is required for macrophage accumulation and parasite eradication in the recipient mice. We also found that IL-17 induces CCL2/7, which recruit macrophages. Our findings reveal a novel protective mechanism whereby IL-23, IL-17, and macrophages reduce the severity of infection with blood-stage malaria parasites. Keywords: IL-17 · IL-23 · Macrophage · Malaria · Plasmodium bergheiAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionMalaria, caused by protozoan parasites of the genus Plasmodium, is still one of the most life-threatening infectious diseases. Two hundred million people are infected annually with malaria paraCorrespondence: Dr. Hajime Hisaeda e-mail: hisa@med.gunma-u.ac.jp sites while about a million people are believed to die every year from the disease [1]. Despite the urgent need for effective vaccines against malaria, progress on vaccine development has been disappointing [2]. A major obstacle for vaccine development is that the immune responses crucial for eradication of malaria * These authors contributed equally to this work. parasites are not fully understood. Another concern is that infection with Plasmodium falciparum, which causes the most severe form of the disease in young children and pregnant women, can lead to pathological inflammation resulting in severe complications, such as cerebral malaria. Thus, to succeed in developing an effective vaccine against malaria, it is crucial that the mechanisms underlying protective immunity as well as those that drive pathogenic responses are better understood.IL-23 is a proinflammatory cytokine that belongs to IL-12 cytokine family. It is a heterodimeric molecule composed of p40 and p19 subunits [3]. The proinflammatory activities of IL-23 are responsible for the onset not only of autoimmune diseases such as rheumatoid arthritis and multiple sclerosis [4,5], but also infection-induced pathological consequences of infection with the pathogens causing Lyme disease and ...

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Interleukin‐17 and its target genes: mechanisms of interleukin‐17 function in disease

Cited by 784 publications

References 131 publications

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Lactobacillus paracasei and Lactobacillus plantarum strains downregulate proinflammatory genes in an ex vivo system of cultured human colonic mucosa

Inflammatory Cytokines IL-32 and IL-17 Have Common Signaling Intermediates despite Differential Dependence on TNF-Receptor 1

IL‐23 protection against Plasmodium berghei infection in mice is partially dependent on IL‐17 from macrophages

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