Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Taleb, Soraya; Romain, Mélissa; Ramkhelawon, Bhama; Uyttenhove, Catherine; Pasterkamp, Gérard; Herbin, Olivier; Esposito, Bruno; Pérez, Nicolas; Yasukawa, Hideo; Snick, Jacques Van; Yoshimura, Akihiko; Tedgui, Alain; Mallat, Ziad

doi:10.1083/jcb1866oia11

Cited by 46 publications

(78 citation statements)

References 34 publications

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“…There are conflicting reports about the role of SOCS3 in Th17‐type cytokine production. Some investigators found that TGF‐β inhibits SOCS3 to enhance Th17‐cell development and overexpression of SOCS3 in T‐lymphocytes impairs IL‐17 production . On the other hand, one study showed that increased SOCS3 expression in CD4 + T cells increased IL‐17 production .…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection

et al. 2014

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SUMMARY We studied the factors that regulate IL-23 receptor expression and IL-17 production in human tuberculosis infection. Mycobacterium tuberculosis (M. tb)-stimulated CD4+ cells from tuberculosis patients secreted less IL-17 than did CD4+ cells from healthy tuberculin reactors (PPD+). M. tb cultured monocytes from tuberculosis patients and PPD+ donors expressed equal amounts of IL-23p19 mRNA and protein, suggesting that reduced IL-23 production is not responsible for decreased IL-17 production by tuberculosis patients. Freshly isolated and M. tb- stimulated CD4+ cells from tuberculosis patients had reduced IL-23 receptor and phosphorylated STAT3 (pSTAT3) expression, compared to PPD+ donors. STAT3 siRNA reduced IL-23 receptor expression, and IL-17 production by CD4+ cells from PPD+ donors. Tuberculosis patients had increased number of PD-1+ T cells compared to healthy PPD+ individuals. Anti-PD-1 antibody enhanced pSTAT3 and IL-23R expression and IL-17 production by M. tb cultured CD4+ cells of tuberculosis patients. Anti-tuberculosis therapy decreased PD-1 expression, increased IL-17 and IFN-γ production and pSTAT3, IL-23R expression. These findings demonstrate that increased PD-1 expression and decreased pSTAT3 expression reduces IL-23 receptor expression and IL-17 production by CD4+ cells of tuberculosis patients.

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Section: Discussionmentioning

confidence: 99%

Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection

et al. 2014

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“…There is some controversy surrounding the role of SOCS3 in the regulation of IL‐17 production. While evidence indicates that SOCS3 is a negative regulator of STAT‐3 activation , resulting in the reduction of its downstream target IL‐17 , an isolated research paper investigating human T cells has reported that SOCS3 expression promotes IL‐17 production. It may be of relevance to note that the authors, being unable to down‐regulate SOCS3 using short hairpin RNA, ultimately suppressed the gene with recombinant IL‐7.…”

Section: Discussionmentioning

confidence: 99%

“…In so doing it attenuates the production of IL‐17 from T helper type 17 (Th17) cells , a process that is dependent upon STAT‐3 activation . Several studies have demonstrated that SOCS3 expression correlates inversely with that of pSTAT‐3 and that of IL‐17 .…”

Section: Introductionmentioning

confidence: 99%

Dysregulation of the suppressor of cytokine signalling 3–signal transducer and activator of transcription-3 pathway in the aetiopathogenesis of Sjögren's syndrome

Vartoukian

Tilakaratne

Seoudi

et al. 2014

Clinical and Experimental Immunology

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SummaryThe suppressor of cytokine signalling 3 (SOCS3) negatively regulates the Janus kinase (JAK)/signal transducer and activator of transcription-3 (STAT-3)/interleukin (IL)-17 pathway. The proinflammatory cytokine IL-17 is overexpressed in Sjögren's syndrome (SS) and is a key factor in its pathogenesis. We hypothesized that IL-17 over-expression in SS results from ineffective regulation by SOCS3. The expression of SOCS3 was analysed in peripheral blood mononuclear cells (PBMC) from SS cases, sicca controls (SC) and healthy controls (HC) and tissue samples from SS, SC and healthy salivary glands (HSG). PBMC and salivary gland tissue from SS and controls were dual-immunostained for SOCS3 and IL-17. IL-6-stimulated PBMC from SS and controls were evaluated for time-dependent STAT-3 activation and SOCS3 induction, and for IL-17 expression. Immunoblotting revealed greater levels of SOCS3 in PBMC from SS than SC (P = 0·017) or HC (P < 0·001). Similarly, the proportion of salivary-gland tissue cells staining for SOCS3 was significantly higher in SS than SC (P = 0·029) or HSG (P = 0·021). The cells in PBMC/salivary gland samples from controls predominantly expressed either SOCS3 or IL-17. However, there was a high frequency of SOCS3/IL-17 co-expression within cells of SS samples. IL-6-stimulation of PBMC from SS cases revealed prolonged activation of STAT-3 with reduced negative regulation by SOCS3, and enhanced expression of IL-17. This study showed that SOCS3 expression is up-regulated in SS. However, the absence in SS of the normal inverse relationship between SOCS3 and pSTAT-3/IL-17 indicates a functional disturbance in this signalling cascade. Consequently, a reduction in function, rather than a reduction in expression of SOCS3 accounts for the unregulated expression of IL-17 in SS, and may play a crucial role in aetiopathogenesis.

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“…The acceleration of the disease was observed in Il17A −/− Apoe −/− mice, where increased IFN‐γ and reduced IL‐5 production was suggested as a potential mechanism . Mice deficient in the suppressor of cytokine signaling 3 (SOCS3) in T cells have significantly reduced atherosclerosis, which correlates with enhanced production of IL‐17A (but also IL‐10), indirectly implying an atheroprotective effect of IL‐17A . However, the majority of reports suggest a pro‐atherogenic role for IL‐17A.…”

Section: Specific Roles For Cytokines In Atherosclerosis and Aaamentioning

confidence: 99%

Atherosclerosis and aortic aneurysm – is inflammation a common denominator?

2016

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Cardiovascular diseases (CVD) are the major cause of death in developed countries. Various risk factors including host genetics and, more importantly, environmental factors such as lifestyle, diet and smoking influence CVD progression. Two common forms of CVD are atherosclerosis and abdominal aortic aneurysm (AAA). Emerging evidence suggests that inflammation plays a pivotal role in CVD. However, it remains unclear whether the same inflammatory pathways prove essential for atherosclerosis and AAA because, in some cases, the same mechanisms uniformly promote both diseases, while in others they function in opposite ways. Cytokines, key mediators of inflammation, play an important role in the development of atherosclerosis but have only been scarcely studied in AAA. In this review, we discuss the importance of immune‐mediated mechanisms and cytokines in the pathogenesis of atherosclerosis and AAA.

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Loss of SOCS3 expression in T cells reveals a regulatory role for interleukin-17 in atherosclerosis

Cited by 46 publications

References 34 publications

Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection

Phosphorylated STAT3 and PD‐1 regulate IL‐17 production and IL‐23 receptor expression in Mycobacterium tuberculosis infection

Dysregulation of the suppressor of cytokine signalling 3–signal transducer and activator of transcription-3 pathway in the aetiopathogenesis of Sjögren's syndrome

Atherosclerosis and aortic aneurysm – is inflammation a common denominator?

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