VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts

Gutiérrez‐Cañas, Irene; Juarranz, Yasmina; Santiago, Begoña; Arranz, Alicia; Martı́nez, Carmen; Galindo, María; Payá, Monica; Gomariz, Rosa P.; Pablos, José L.

doi:10.1093/rheumatology/kei219

Cited by 76 publications

(66 citation statements)

References 40 publications

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“…Several studies in the murine model of collagen-induced arthritis have shown that VIP or PACAP potently inhibits inflammatory and autoimmune components, protecting the joints from structural damage (5,6,28). Our previous findings in human synovial cells confirm some antiinflammatory effects of VIP under both constitutive and TNF␣-or Toll-like receptor 4-stimulated conditions (12,29). A less developed concept is the potential endogenous participation of these neuropeptides in the pathogenesis of inflammation, either as endogenous mediators counterbalancing proinflammatory signaling or as permissive factors, if they are down-regulated during inflammatory responses.…”

Section: Discussionsupporting

confidence: 74%

“…Although clinical trials of VIP or related neuropeptides in human inflammatory diseases have not been performed, our previous studies demonstrated that exogenous VIP modulates different proinflammatory pathways ex vivo in human rheumatoid arthritis (RA) synovial cells (11,12). The detection of several neuropeptides, including VIP, in human arthritic joints suggests that endogenous VIP might play a regulatory role in response to joint inflammation (13,14).…”

mentioning

confidence: 99%

“…These cells produce a variety of mediators such as chemokines, cytokines, and cellsurface molecules that contribute to the chronic inflammatory process and to bone and cartilage destruction. According to previous studies by our group and by other investigators, VIP antiinflammatory signaling is functional in human FLS, but the ability of these cells to synthesize VIP or to regulate VIP or VIP receptor expression under inflammatory conditions has not been investigated (11,12). Alternatively, because VIP and related neuropeptides are short-lived peptides, identification of specific antiinflammatory signaling receptors in relevant human cellular models is needed to develop antiinflammatory VIP agonists.…”

mentioning

confidence: 99%

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Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Juarranz

Gutiérrez‐Cañas

Santiago

et al. 2008

Arthritis & Rheumatism

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Objective. Vasoactive intestinal peptide (VIP) hasshown potent antiinflammatory effects in murine arthritis and ex vivo in human rheumatoid arthritis (RA) synovial cells. To investigate the potential endogenous participation of this system in the pathogenesis of RA, we analyzed the expression and regulation of VIP and its functional receptors in human fibroblast-like synoviocytes (FLS) from patients with osteoarthritis (OA) and patients with RA.Methods. The expression of VIP was studied by reverse transcription-polymerase chain reaction (RT-PCR), enzyme immunoassay, and immunofluorescence in cultured FLS, and by immunohistochemical analysis in synovial tissue. The expression and function of the potential VIP receptors in FLS were studied by RT-PCR, determination of intracellular cAMP production, cell membrane adenylate cyclase (AC) activity, and interleukin-6, CCL2, and CXCL8 production in response to VIP or specific agonists and antagonists.Results. VIP expression was detected in human FLS at the messenger RNA and protein levels, and it was significantly decreased in RA FLS compared with OA FLS. VIP receptor type 1 (VPAC 1 ) was the dominant AC-coupled receptor in OA FLS, in contrast with RA FLS, in which VPAC 2 was dominant. Tumor necrosis factor ␣-treated OA FLS reproduced the VIP and VPAC receptor expression pattern of RA FLS. The antagonistic effects of VIP on FLS proinflammatory factor production were reproduced by VPAC 1 -and VPAC 2 -specific agonists in OA FLS and RA FLS, respectively.Conclusion. VIP expression is down-regulated in RA and in tumor necrosis factor ␣-treated FLS, suggesting that down-regulation of this endogenous antiinflammatory factor may contribute to the pathogenesis of RA. In RA FLS, VPAC 2 mediates the antiinflammatory effects of VIP, suggesting that VPAC 2 agonists may be an alternative to VIP as antiinflammatory agents.The vasoactive intestinal peptide (VIP)/pituitary adenylate cyclase-activating peptide (PACAP) system consists of 2 peptides and 3 receptors: VIP receptor type 1 (VPAC 1 ), VPAC 2 , and PACAP type 1 (PAC 1 ) receptor. These receptors belong to family 2 of the G proteincoupled receptors, which in recent years have shown remarkable antiinflammatory and immunomodulatory properties (1-3). VPAC 1 is constitutively expressed in macrophages and lymphocytes and binds VIP and PACAP with equal affinity (1,3). VPAC 2 has also been described in lymphocytes and macrophages as an inducible receptor after T cell receptor triggering or lipopolysaccharide (LPS) stimulation (1,3). The bestcharacterized effects of VIP/PACAP on immune cells are mediated by the adenylate cyclase (AC) pathway coupled to these receptors. Finally, the PAC 1 receptor is the PACAP-specific receptor, although at high concentrations VIP is a heterologous ligand (4). Endogenous VIP and PACAP can be produced by both neural and immune cells, but their regulation and participation in the pathogenesis of human inflammation are not known.

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Section: Discussionsupporting

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Juarranz

Gutiérrez‐Cañas

Santiago

et al. 2008

Arthritis & Rheumatism

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“…These results are in agreement with the higher expression of Wnt responsive genes, such as WISP1, in OA, 47 which has been associated with a profibrotic and antichondrogenic OA-like phenotype. 48 This…”

Section: Q17mentioning

confidence: 99%

“…50 Thus, in addition to integrins, Fn-fs, as an endogenous ligand of Toll-like receptors 2 and 4, could act through its engagement, given that both receptors are present in SF. 48,51 Moreover, both stimuli induce the activation of MAPK signaling, implicated in the activation of Runx2 and other transcription factors, such as the NF-kB, 13e15,46,52 which also induce the expression of Wnt. 53,54 Therefore, we can hypothesize that IL-1b and 45-kDa Fn-fs induce aggrecanases expression by activation of the transcription factor Runx2, mainly through the ERK-MAPK signaling.…”

Section: Q18mentioning

confidence: 99%

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

Pérez‐García

Gutiérrez‐Cañas

Seoane

et al. 2016

The American Journal of Pathology

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Current description of osteoarthritis includes the involvement of synovial inflammation. Studies contributing to understanding the mechanisms of cross-talk and feedback among the joint tissues could be relevant to the development of therapies that block disease progression. During osteoarthritis, synovial fibroblasts exposed to anomalous mechanical forces and an inflammatory microenvironment release factors such as a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) metalloproteinases that mediate tissue damage and perpetuate inflammation. We therefore studied the production of ADAMTS by synovial fibroblasts and their contribution to cartilage degradation. Moreover, we analyzed the implication of two mediators present in the osteoarthritis joint, IL-1b as proinflammatory cytokine, and 45-kDa fibronectin fragments as products of matrix degradation. We reported that synovial fibroblasts constitutively express and release ADAMTS 4, 5, 7, and 12. Despite the contribution of both mediators to the stimulation of Runx2 and Wnt/b-catenin signaling pathways, as well as to ADAMTS expression, promoting the degradation of aggrecan and cartilage oligomeric matrix protein from cartilage, fibronectin fragments rather than IL-1b played the major pathological role in osteoarthritis, contributing to the maintenance of the disease. Moreover, higher levels of ADAMTS 4 and 7 and a specific regulation of ADAMTS-12 were observed in osteoarthritis, suggesting them as new potential therapeutic targets. Therefore, synovial fibroblasts provide the biochemical tools to the chronicity and destruction of the osteoarthritic joints. (Am J Pathol 2016, -: 1e13; http:// dx

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RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: Immune regulation by vasoactive intestinal peptide

Carrión¹,

Juarranz²,

Pérez‐García³

et al. 2011

Arthritis & Rheumatism

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VIP down-regulates TLR4 expression and TLR4-mediated chemokine production in human rheumatoid synovial fibroblasts

Cited by 76 publications

References 40 publications

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Differential expression of vasoactive intestinal peptide and its functional receptors in human osteoarthritic and rheumatoid synovial fibroblasts

Healthy and Osteoarthritic Synovial Fibroblasts Produce a Disintegrin and Metalloproteinase with Thrombospondin Motifs 4, 5, 7, and 12

RNA sensors in human osteoarthritis and rheumatoid arthritis synovial fibroblasts: Immune regulation by vasoactive intestinal peptide

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