Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases

Amin, M. Asif; Rabquer, Bradley J.; Mansfield, Pamela J.; Ruth, Jeffrey H.; Marotte, Hubert; Haas, Christian; Reamer, Elyse; Koch, Alisa E.

doi:10.1136/ard.2009.127241

Cited by 55 publications

(39 citation statements)

References 37 publications

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“…Interestingly, a number of factors are secreted from RA fibroblasts in response to IL-18 stimulation which consist of adhesion molecules (VCAM1, ICAM1), neutrophil chemoattractants (CXCL1, CXCL5, CXCL12), monocyte chemoattractants (CCL2, CXCL20) and proangiogenic factors (VEGF, IL-8), suggesting that IL-18 can contribute to RA pathogenesis through different mechanisms [87]. Early in disease, IL-18 promotes neutrophil migration [88] and during active disease, myeloid cells are recruited into the joints [89] and inflammation progresses by triggering angiogenesis [90,91]. In addition to IL-18 indirect effects on monocyte and endothelial cell migration [92-94], data obtained from our group of investigators, reveal that IL-18 present in RA synovial fluid can directly attract myeloid and endothelial cells into the inflamed joint [89,91].…”

Section: Introductionmentioning

confidence: 99%

The pathogenic role of angiogenesis in rheumatoid arthritis

Elshabrawy

Chen

Volin³

et al. 2015

Angiogenesis

439

284

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Angiogenesis is the formation of new capillaries from pre-existing vasculature, which plays a critical role in the pathogenesis of several inflammatory autoimmune diseases such as rheumatoid arthritis (RA), spondyloarthropathies, psoriasis, systemic lupus erythematosus, systemic sclerosis and atherosclerosis. In RA, excessive migration of circulating leukocytes into the inflamed joint necessitates formation of new blood vessels to provide nutrients and oxygen to the hypertrophic joint. The dominance of the pro-angiogenic factors over the endogenous angiostatic mediators triggers angiogenesis. In this review article, we highlight the underlying mechanisms by which cells present in the RA synovial tissue are modulated to secrete pro-angiogenic factors. We focus on the significance of pro-angiogenic factors such as growth factors, hypoxia inducible factors, cytokines, chemokines, matrix metalloproteinase and adhesion molecules on RA pathogenesis. As pro-angiogenic factors are primarily produced from RA synovial tissue macrophages and fibroblasts, we emphasize the key role of RA synovial tissue lining layer in maintaining synovitis through neovascularization. Lastly, we summarize the specific approaches utilized to target angiogenesis. We conclude that the formation of new blood vessels plays an indispensable role in RA progression. However since the function of several pro-angiogenic mediators is cross regulated, discovering novel approaches to target multiple cascades or selecting an upstream cascade that impairs the activity of a number of pro-angiogenic factors may provide a promising strategy for RA therapy.

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Section: Introductionmentioning

confidence: 99%

The pathogenic role of angiogenesis in rheumatoid arthritis

Elshabrawy

Chen

Volin³

et al. 2015

Angiogenesis

439

284

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“…4), and thus form receptors truncated at a similar point as IL-1R2 and the putative human type II IL-18R α . While there is no evidence that IL-1R2 can induce JNK signalling, a number of studies have shown IL-18 is able to activate JNK signalling (Chandrasekar et al, 2005; Sahar et al, 2005; Seenu Reddy et al, 2010; Amin et al, 2010). The question which then arises is whether a truncated receptor for IL-18 would still be capable of inducing JNK signalling, as appears to be the case for a truncated IL1RAPL1 receptor.…”

Section: Resultsmentioning

confidence: 99%

Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

Booker

Grattan

2014

PeerJ

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Interleukin-18 (IL-18) is a pro-inflammatory cytokine which stimulates activation of the nuclear factor kappa beta (NF-κB) pathway via interaction with the IL-18 receptor. The receptor itself is formed from a dimer of two subunits, with the ligand-binding IL-18Rα subunit being encoded by the IL18R1 gene. A splice variant of murine IL18r1, which has been previously described, is formed by transcription of an unspliced intron (forming a ‘type II’ IL18r1 transcript) and is predicted to encode a receptor with a truncated intracellular domain lacking the capacity to generate downstream signalling. In order to examine the relevance of this finding to human IL-18 function, we assessed the presence of a homologous transcript by reverse transcription-polymerase chain reaction (RT-PCR) in the human and rat as another common laboratory animal. We present evidence for type II IL18R1 transcripts in both species. While the mouse and rat transcripts are predicted to encode a truncated receptor with a novel 5 amino acid C-terminal domain, the human sequence is predicted to encode a truncated protein with a novel 22 amino acid sequence bearing resemblance to the ‘Box 1’ motif of the Toll/interleukin-1 receptor (TIR) domain, in a similar fashion to the inhibitory interleukin-1 receptor 2. Given that transcripts from these three species are all formed by inclusion of homologous unspliced intronic regions, an analysis of homologous introns across a wider array of 33 species with available IL18R1 gene records was performed, which suggests similar transcripts may encode truncated type II IL-18Rα subunits in other species. This splice variant may represent a conserved evolutionary mechanism for regulating IL-18 activity.

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“…IL-18 plays an important role in the induction of the Th1 response and it may be responsible for BBS progression and granuloma formation. Moreover, it plays a pivotal role in linking inflammatory immune responses and angiogenesis in pulmonary BBS (Amin et al 2010).…”

Section: Discussionmentioning

confidence: 99%

Endostatin and Cathepsin-V in Bronchoalveolar Lavage Fluid of Patients with Pulmonary Sarcoidosis

Naumnik

Ossolińska

Płońska

et al. 2014

Advances in Experimental Medicine and Biology

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Recently, it has been reported that lack of cathepsins prevent the development of lung granulomas in a mouse model of Besnier-Boeck-Schaumann (BBS) disease, sarcoidosis. There is no data about cathepsin V (Cath V) in bronchoalveolar lavage fluid (BALF) in humans. Endostatin is a novel inhibitor of lung epithelial cells. The role of this protein in BBS is not determined. The aim of this study was to evaluate the concentration of endostatin, Cath V, and IL-18 in BALF of BBS patients. We studied 22 BBS patients (Stage 2). The control group consisted of 20 healthy subjects. Cath V concentration was lower in BBS than in healthy group (16.03±8.60 vs. 32.25±21.90 pg/ml, p=0.004). Both endostatin and IL-18 levels were higher in BBS than in the control group (0.88±0.30 vs. 0.29±0.04 ng/ml, p=0.028; 40.37±31.60 vs. 14.61±1.30 pg/ml, p=0.007, respectively). In BBS there were correlations between the levels of endostatin and IL-18 (r=0.74, p=0.001) as well as endostatin and DLCO (diffusing capacity for carbon monoxide) (r=-0.6, p=0.013). Receiver-operating characteristic (ROC) curves were applied to find the cut-off for the BALF levels of Cath V, endostatin, and IL-18. We conclude that Cath V and endostatin may represent an index of pulmonary sarcoidosis activity.

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Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases

Abstract: Targeting IL-18 or its signalling intermediates may prove to be a potentially novel therapeutic strategy for angiogenesis-dependent diseases, such as RA.

Cited by 55 publications

References 37 publications

The pathogenic role of angiogenesis in rheumatoid arthritis

The pathogenic role of angiogenesis in rheumatoid arthritis

Identification of a truncated splice variant of IL-18 receptor alpha in the human and rat, with evidence of wider evolutionary conservation

Endostatin and Cathepsin-V in Bronchoalveolar Lavage Fluid of Patients with Pulmonary Sarcoidosis

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