Serum levels of C1q/TNF‐related protein‐3 in inflammatory bowel disease patients and its inverse association with inflammatory cytokines and insulin resistance

Mohamadinarab, Maryam; Ahmadi, Reza; Gholamrezayi, Afsane; Rahvar, Farzaneh; Naghdalipour, Mehri; Setayesh, Leila; Fadaei, Reza; Chamani, Elham; Tavakoli, Tahmine; Esteghamati, Abdoulreza

doi:10.1002/iub.2293

Cited by 11 publications

(14 citation statements)

References 21 publications

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“…We have already shown that CTRP3 ameliorates development of autoimmune arthritis (21). Furthermore, CTRP3 is implicated in the regulation of myocardiac dysfunction, inflammatory bowel disease, severe acute pancreatitis and chronic kidney diseases (21)(22)(23)(24)(25). Because involvement of Th17 cells is suggested in these diseases (72)(73)(74)(75), it is possible that CTRP3 regulates excess inflammation in these diseases.…”

Section: Discussionmentioning

confidence: 99%

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The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

et al. 2021

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C1q/TNF-related proteins (CTRP) including CTRP3 are a group of secreted proteins which have a complement C1q-like domain in common, and play versatile roles in lipid metabolism, inflammation, tumor metastasis and bone metabolism. Previously, we showed that the expression of C1qtnf3, encoding CTRP3, is highly augmented in joints of autoimmune arthritis models and CTRP3-deficiency exacerbates collagen-induced arthritis in mice. However, the mechanisms how CTRP3-deficiency exacerbates arthritis still remain to be elucidated. In this study, we showed that CTRP3 was highly expressed in Th17 cell, a key player for the development of autoimmune diseases, and Th17 cell differentiation was augmented in C1qtnf3–/– mice. Th17 cell differentiation, but not Th1 cell differentiation, was suppressed by CTRP3 and this suppression was abolished by the treatment with a receptor antagonist against AdipoR2, but not AdipoR1, associated with suppression of Rorc and Stat3 expression. Furthermore, AdipoR1 and AdipoR2 agonist, AdipoRon suppressed Th17 cell differentiation via AdipoR2, but not AdipoR1. The development of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis was enhanced in C1qtnf3–/– mice associated with increase of Th17 cell population. CTRP3 inhibited MOG-induced IL-17 production from T cells by affecting both T cells and dendritic cells. These results show that CTRP3 is an endogenous regulator of Th17 differentiation, suggesting that the CTRP3-AdipoR2 axis is a good target for the treatment of Th17 cell-mediated diseases.

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Section: Discussionmentioning

confidence: 99%

“…CTRP3 is implicated in the development of myocardiac dysfunction, inflammatory bowel diseases, severe acute pancreatitis and chronic kidney diseases (22)(23)(24)(25). CTRP3 also functions as an antagonist for LPS, and modulates antiinflammatory functions of monocytes, macrophages, adipocytes and fibroblasts (26)(27)(28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

et al. 2021

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“…In the human study, CTRP3 significantly inhibits the production of IL-6 induced by LPS in monocytes derived from healthy controls, but CTRP3 had no such effect on IL-6 in monocytes isolated from diabetic patients (Alberti and Zimmet, 1998;Cherrington, 1999). Additionally, CTRP3 also influences some specific inflammatory disorders, such as immunoglobulin A nephropathy (Zhang et al, 2016) and inflammatory bowel disease (Zhang et al, 2016;Mohamadinarab et al, 2020). Overall, CTRP-3 is a promising target for the treatment of chronic low-grade inflammationrelated diseases.…”

Section: Ctrp3 In Obesity and Metabolic Syndromementioning

confidence: 94%

New Insights Into Implications of CTRP3 in Obesity, Metabolic Dysfunction, and Cardiovascular Diseases: Potential of Therapeutic Interventions

Guo

Zhuang

et al. 2020

Front. Physiol.

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Adipose tissue, as the largest endocrine organ, secretes many biologically active molecules circulating in the bloodstream, collectively termed adipocytokines, which not only regulate the metabolism but also play a role in pathophysiological processes. C1q tumor necrosis factor (TNF)-related protein 3 (CTRP3) is a member of C1q tumor necrosis factor-related proteins (CTRPs), which is a paralog of adiponectin. CTRP3 has a wide range of effects on glucose/lipid metabolism, inflammation, and contributes to cardiovascular protection. In this review, we comprehensively discussed the latest research on CTRP3 in obesity, diabetes, metabolic syndrome, and cardiovascular diseases.

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“…48,49 Notably, the serum levels of CTRP3 are reduced in IBD patients. 50 The function of CTRP3 in IBD, however, has not previously been established.…”

Section: Introductionmentioning

confidence: 99%

Adipokine C1q/Tumor necrosis factor-Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation via Histone Deacetylase Sirtuin 1 (SIRT1)/NF-κB Signaling

Zhang

et al. 2022

Preprint

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BACKGROUND & AIMSThe adipokine C1q/tumor necrosis factor-related protein 3 (CTRP3) has anti-inflammatory effects in several non-intestinal disorders. Although CTRP3 is reduced in the serum of patients with inflammatory bowel disease (IBD), its function in IBD has not been established. We aimed to elucidate the function of CTRP3 and related molecular mechanisms in intestinal inflammation using a colitis model of genetically-modified CTRP3 mice and intestinal epithelial tissue from patients with Crohn’s disease (CD), one of the two main forms of IBD.METHODSCTRP3 knockout (KO) and overexpressing transgenic (Tg) mice along with their corresponding wild-type (WT) littermates were subjected to drinking water containing dextran sulfate sodium (DSS) for 6-10 days to induce acute colitis. Mouse colitis symptoms and histological data were analyzed. CTRP3-mediated signaling was examined in the intestinal tissue of mice and patients with CD.RESULTSCTRP3 mRNA and protein were detected in murine and human intestinal epithelial cells, as well as in murine intestinal smooth muscle cells and mesenteric fat. In DSS-induced acute colitis models, CTRP3 KO mice developed more severe colitis than their WT littermates, while CTRP3 overexpressing Tg mice developed less severe colitis than their WT littermates. In both water- and DSS-treated CTRP3 KO mice, reduced CTRP3 levels correlated with decreased levels of Sirtuin 1 (SIRT1), a histone deacetylase, increased levels of phosphorylated nuclear factor kappa B (NF-κB) subunit p65, resulting in increased expression of pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). The results from CTRP3 Tg mice mirrored those from CTRP3 KO mice in most respects. This CTRP3/SIRT1/NF-κB relationship was also observed in the intestinal epithelial tissue of patients with active and inactive CD.CONCLUSIONSCTRP3 expression levels correlate negatively with intestinal inflammation in mouse colitis models and CD patients. CTRP3 attenuates intestinal inflammation via SIRT1/NF-κB signaling to suppress pro-inflammatory cytokines in mouse colitis models and patients with IBD. The manipulation of CTRP3 signaling, including through the use of SIRT1 agonists, may offer translational potential in the treatment of IBD.WHAT YOU NEED TO KNOWBACKGROUND AND CONTEXTAdipokine C1q/tumor necrosis factor-related protein 3 (CTRP3) is a novel adipokine with known non-intestinal anti-inflammatory effects. CTRP3 is reduced in the serum of patients with inflammatory bowel disease (IBD). However, little is known about whether and how CTRP3 influences intestinal inflammation in IBD.NEW FINDINGSCTRP3 mRNA and protein were detected in murine and human intestinal epithelial cells, as well as in murine intestinal smooth muscle cells and mesenteric fat. CTRP3 deletion was associated with more severe acute dextran sulfate sodium (DSS)-induced colitis, while CTRP3 overexpression was associated with less severe colitis. In both mice and humans, reduced CTRP3 levels correlated with reduced levels of the histone deacetylase Sirtuin 1 (SIRT1), resulting in the up-regulation of phosphorylated nuclear factor-kappa B (NF-κB) p65 and pro-inflammatory cytokine synthesis.LIMITATIONSThis study was performed using genetically modified mice and human tissue samples. An acute DSS-induced colitis model was used; additional mouse colitis models designed to mimic other aspects of IBD will be examined in future studies. The specific source of the secreted CTRP3 protein which influences intestinal inflammation is yet to be identified. The use of recombinant CTRP3 protein supplementation and SIRT1 agonists to mitigate intestinal inflammation also requires further study.IMPACTCTRP3 is a novel anti-inflammatory adipokine that attenuates intestinal inflammation in colitis mouse models and intestinal epithelial tissue of patients with IBD. CTRP3 attenuates intestinal inflammation by activating SIRT1, which suppresses the pro-inflammatory transcriptional activity of phosphorylated NF-κB p65. CTRP3 and SIRT1 agonists have potential as novel IBD drug targets.

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Serum levels of C1q/TNF‐related protein‐3 in inflammatory bowel disease patients and its inverse association with inflammatory cytokines and insulin resistance

Cited by 11 publications

References 21 publications

The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

The CTRP3-AdipoR2 Axis Regulates the Development of Experimental Autoimmune Encephalomyelitis by Suppressing Th17 Cell Differentiation

New Insights Into Implications of CTRP3 in Obesity, Metabolic Dysfunction, and Cardiovascular Diseases: Potential of Therapeutic Interventions

Adipokine C1q/Tumor necrosis factor-Related Protein 3 (CTRP3) Attenuates Intestinal Inflammation via Histone Deacetylase Sirtuin 1 (SIRT1)/NF-κB Signaling

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