Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells

Juarranz, Marı́a G.; Santiago, Begoña; Torroba, M.; Gutiérrez‐Cañas, Irene; Palao, Guillermo; Galindo, María; Abad, Catalina; Martı́nez, Carmen; Leceta, Javier; Pablos, José L.; Gomariz, Rosa P.

doi:10.1093/rheumatology/keh061

Cited by 65 publications

(61 citation statements)

References 22 publications

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“…The sequences of the primers used and the accession numbers of the genes analyzed are summarized in Table 1. For relative quantification, we compared the amount of target normalized to an endogenous reference, using the formula 2 -⌬⌬Ct , as previously described (11). The levels of VIP in concentrated FLS culture supernatants were also measured by EIA, using a commercial kit (Phoenix Pharmaceuticals, Karlsruhe, Germany) according to the manufacturer's instructions.…”

Section: Methodsmentioning

confidence: 99%

“…The amounts of interleukin-6 (IL-6), chemokine (CC motif) ligand 2 (CCL2; monocyte chemoattractant protein 1 [MCP-1]), and chemokine (CXC motif) ligand 8 (CXCL8; IL-8) in the supernatants of FLS cultures treated with 100 nM VIP, VPAC 1 agonist, or VPAC 2 agonist for 24 hours were determined with a human capture ELISA, as previously described (11). Both the intraassay and interassay variability for cytokine and chemokines determination were Ͻ5%.…”

Section: Methodsmentioning

confidence: 99%

“…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: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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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“…Moreover, increased serum levels of IL-6 and IL-8 have been detected in patients with chronic obstructive pulmonary diseases, and chemokines such as IL-8 and RANTES play important roles in the pathogenesis of these diseases (35,36). Various inflammatory mediators, such as IL-1, TNF-␣, IL-6, IL-8, RANTES, and MMP-3, are responsible for chronic inflammatory rheumatoid diseases such as osteoarthritis and rheumatoid arthritis, both of which occur during aging (37). The observation that the senescence-associated molecule hPNPase old-35 induces proinflammatory cytokines that are intimately involved in the development of aging-associated diseases suggests a potential involvement of hPNPase old-35 in these pathological processes.…”

Section: Old-35mentioning

confidence: 99%

Human Polynucleotide Phosphorylase ( hPNPase old-35 )

Sarkar¹,

Lebedeva²,

Emdad³

et al. 2004

Cancer Research

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Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

Rey¹,

Izquierdo²,

Caja³

et al. 2009

Arthritis & Rheumatism

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Objective. Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis.Methods. Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice. Cell infiltration and angiogenesis were analyzed in the grafts by immunohistochemical studies. The role of vascular endothelial growth factor (VEGF), CXCL12, and hypoxia-inducible transcription factor 1␣ (HIF-1␣) in these processes was investigated using specific antagonists or small interfering RNA (siRNA)-mediated down-regulation of HIF-1␣ in fibroblasts.Results. Inflammatory (OA and RA) synovial fibroblasts, compared with healthy dermal or synovial tissue fibroblasts, induced a significant enhancement in myeloid cell infiltration and angiogenesis in immunodeficient mice. These activities were associated with increased constitutive and hypoxia-induced expression of VEGF, but not CXCL12, in inflammatory fibroblasts compared with healthy fibroblasts. VEGF and CXCL12 antagonists significantly reduced myeloid cell infiltration and angiogenesis. Furthermore, targeting of HIF-1␣ expression by siRNA or of HIF-1␣ transcriptional activity by the small molecule chetomin in RA fibroblasts significantly reduced both responses.Conclusion. These results demonstrate that chronic synovial inflammation is associated with stable fibroblast changes that, under hypoxic conditions, are sufficient to induce inflammatory cell recruitment and angiogenesis, both of which are processes relevant to the perpetuation of chronic inflammation.Fibroblasts are ubiquitous mesenchymal cells with vital functions during development and adulthood. They synthesize the extracellular matrix components of connective tissues needed for homeostasis and reparative responses. During development, interactions between mesenchymal and other cell lineages are necessary for the formation of many organs, and fibroblasts are sufficient to provide the positional cues required for the induction and development of the different tissues (1,2). In the adult, multiple evidence points to specialized fibroblasts as a major force in the regulation of cell homing, migration, and differentiation of highly dynamic cell populations, such as cells of the immune system or the bone marrow (3,4). With regard to the pathologic

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Vasoactive intestinal peptide modulates proinflammatory mediator synthesis in osteoarthritic and rheumatoid synovial cells

Abstract: Our observations confirm that the proposed anti-inflammatory actions of VIP in murine models also apply to human synovial cells ex vivo. Further studies are encouraged to evaluate the use of VIP as a potential therapy for chronic inflammatory joint diseases.

Cited by 65 publications

References 22 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

Human Polynucleotide Phosphorylase ( hPNPase old-35 )

Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia‐inducible transcription factor 1α/vascular endothelial growth factor–mediated pathway in immunodeficient mice

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