The C-terminal module IV of connective tissue growth factor is a novel immune modulator of the Th17 response

Rodrigues‐Díez, Raquel; Rodrigues-Díez, Raúl R.; Rayego‐Mateos, Sandra; Suárez-Álvarez, Beatriz; Lavoz, Carolina; Aroeira, Luiz Stark; Sánchez-López, Elsa; Orejudo, Macarena; Alique, Matilde; López‐Larrea, Carlos; Ortíz, Alberto; Egido, Jesús; Ruíz-Ortega, Marta

doi:10.1038/labinvest.2013.67

Cited by 44 publications

(69 citation statements)

References 63 publications

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“…Inflammation occurs upon tissue injury and/or invasion of pathogenic factors, which usually causes extra damage to the tissues. According to a recent study, the CT module seems to be a key domain for CCN2 to exert its pro-inflammatory effects [72]. For example, CCN2 is induced by TGF-β and is repressed by tumour necrosis factor (TNF)-α; whereas this gene product induces inflammatory interleukin (IL)-6, MCP1 and ECM-remodelling MMPs [13,[68][69][70].…”

Section: Inflammation Wound Healing and Fibrosismentioning

confidence: 99%

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

2014

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CCN family protein 2 (CCN2), also widely known as connective tissue growth factor (CTGF), is one of the founding members of the CCN family of matricellular proteins. Extensive investigation on CCN2 over decades has revealed the novel molecular action and functional properties of this unique signalling modulator. By its interaction with multiple molecular counterparts, CCN2 yields highly diverse and context-dependent biological outcomes in a variety of microenvironments. Nowadays, CCN2 is recognized to conduct the harmonized development of relevant tissues, such as cartilage and bone, in the skeletal system, by manipulating extracellular signalling molecules involved therein by acting as a hub through a web. However, on the other hand, CCN2 occasionally plays profound roles in major human biological disorders, including fibrosis and malignancies in major organs and tissues, by modulating the actions of key molecules involved in these clinical entities. In this review, the physiological and pathological roles of this unique protein are comprehensively summarized from a molecular network-based viewpoint of CCN2 functionalities.

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Section: Inflammation Wound Healing and Fibrosismentioning

confidence: 99%

Cellular and molecular actions of CCN2/CTGF and its role under physiological and pathological conditions

2014

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“…In PDF-instilled mice, IL-17A immunostaining was also observed in CD4 þ and gd lymphocytes of the submesothelial zone. IL-17A is classically produced by CD4 þ lymphocytes (Th17 cells); however, other sources have been described, including other T-cell subsets, such as gd, natural killer and CD8 þ , 21-23 neutrophils in antineutrophil cytoplasmic antibody-associated glomerulonephritis, 24 dendritic cells under special circumstances, 25 mast cells in chronic rheumatoid arthritis, 26 and tubular cells in transplanted kidneys 27 and in experimental models or renal damage, 28 showing that some resident cells could also produce IL-17A.…”

Section: Discussionmentioning

confidence: 99%

“…28 Protein extracts were studied by enzyme-linked immunosorbent assay (ebioscience) or by western blotting, with primary antibodies against RORgt (ebioscience; 14-6981 dilution 1:1000), phosphorylated STAT3 (Cell Signaling Technology, Danvers, MA; dilution 1:1000), as described, 28 a-SMA (Sigma: A-2547; dilution 1:1000), and FN (Millipore AB2033; dilution 1:10,000). Data were expressed as n-fold increase over the mean of control mice levels.…”

Section: Histology and Immunohistochemistrymentioning

confidence: 99%

IL-17A is a novel player in dialysis-induced peritoneal damage

Rodrigues‐Díez

Aroeira

Orejudo

et al. 2014

Kidney International

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The classical view of the immune system has changed by the discovery of novel T-helper (Th) subsets, including Th17 (IL-17A-producing cells). IL-17A participates in immune-mediated glomerulonephritis and more recently in inflammatory pathologies, including experimental renal injury. Peritoneal dialysis patients present chronic inflammation and Th1/Th2 imbalance, but the role of the Th17 response in peritoneal membrane damage has not been investigated. In peritoneal biopsies from dialyzed patients, IL-17A immunostaining was found mainly in inflammatory areas and was absent in the healthy peritoneum. IL-17A-expressing cells included lymphocytes (CD4+ and γδ), neutrophils, and mast cells. Elevated IL-17A effluent concentrations were found in long-term peritoneal dialysis patients. Studies in mice showed that repeated exposure to recombinant IL-17A caused peritoneal inflammation and fibrosis. Moreover, chronic exposure to dialysis fluids resulted in a peritoneal Th17 response, including elevated IL-17A gene and protein production, submesothelial cell infiltration of IL-17A-expressing cells, and upregulation of Th17 differentiation factors and cytokines. IL-17A neutralization diminished experimental peritoneal inflammation and fibrosis caused by chronic exposure to dialysis fluids in mice. Thus, IL-17A is a key player of peritoneum damage and it may be a good candidate for therapeutic intervention in peritoneal dialysis patients.

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“…In naïve murine CD4 þ T cells, TWEAK promoted Th17 differentiation [20]. Recent studies suggest that blockade of IL-17A is a promising tool for chronic human inflammatory diseases, such as rheumatoid arthritis, uveitis and psoriasis [21][22][23], and in experimental renal damage [24], although there are no data in human renal diseases. In the synovium of rheumatoid arthritis patients, the presence of CD4 þ coexpressing IL-17A and Fn14 was found, and Fn14 blockade suppressed Th17 differentiation and, conversely, enhanced Treg differentiation [20].…”

Section: Tweak a Key Cytokine In Renal Inflammationmentioning

confidence: 99%