MAPKs and their relevance to arthritis and inflammation

Thalhamer, Theresa; McGrath, Mairi; Harnett, Margaret M.

doi:10.1093/rheumatology/kem297

Cited by 414 publications

(318 citation statements)

References 97 publications

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Section: Discussionmentioning

confidence: 99%

“…MAPKs are associated with TNF receptor-family signaling, chemokine-and cytokine-induced signaling events, and Toll-like receptor activation (40,41). In turn, MAPK signaling leads to the expression of proinflammatory cytokines and chemokines, such as TNF␣, IL-1, IL-6, IL-12, and IL-23 (41). Notably, JNK activation early in RA, prior to evidence of fulfillment of the American College of Rheumatology/European League Against Rheumatism criteria (42), is predictive of subsequent erosions (43).…”

Section: Discussionmentioning

confidence: 99%

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Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

Arthritis & Rheumatism

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Objective. Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in joint inflammation. Fibroblast-like synoviocytes in affected joints are responsible for pannus formation and cytokine/ chemokine production, resulting in leukocyte recruitment and bone/cartilage destruction. Previously, we identified a multipotent stem cell population of activated fibrocytes in the blood of patients with RA that may have a role in disease pathogenesis, perhaps as fibroblast-like synoviocyte precursors. The aim of this study was to further characterize the contribution of circulating fibrocytes to the pathogenesis of RA.Methods. Circulating fibrocytes were isolated from mice with collagen-induced arthritis and transferred intravenously into recipient mice with collagen antibody-induced arthritis (CAIA). The activation status of circulating fibrocytes was determined using multidimensional phosphoflow cytometric analysis of the signaling effectors STAT-5, STAT-1, AKT, and JNK. Circulating fibrocyte trafficking and matrix metalloproteinase (MMP) activity were assessed in real time using fluorescence molecular tomography, specifically labeling circulating fibrocytes with CellVue Maroon and measuring MMP activity using MMPSense 680.Results. The numbers of circulating fibrocytes were increased early during the onset of CAIA, concomitant with their activation, as measured by phosphorylation of STAT-5. Adoptive transfer of circulating fibrocytes augmented disease scores and increased class II major histocompatibility complex expression and peripheral blood phosphoactivation profiles in recipient mice with CAIA. Notably, adoptively transferred fluorescence-labeled circulating fibrocytes rapidly migrated into the affected joints of recipient mice with CAIA, and this was associated with augmented neutrophil recruitment into affected joints and MMP activation.Conclusion. Circulating fibrocytes migrate to joints and influence the onset of disease processes in arthritis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Galligan¹,

Fish²

2012

Arthritis & Rheumatism

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“…29 The extracellular signal-regulated kinases (ERKs) and p38 MAPK are two major classes of MAPKs that play important roles in transducing inflammatory signals. 30,31 To determine whether these two pathways are involved in the upregulation of IL-6 and IL-8 in ARPE-19 cells, we examined the activation of signaling molecules by western blotting with phospho-specific antibodies.…”

Section: Induction Of Il-8 By Histones Is Mediated By Erk1/2-and P38 mentioning

confidence: 99%

Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment

Kawano

Ito

Yamada³

et al. 2014

Laboratory Investigation

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Histones are DNA-binding proteins and are involved in chromatin remodeling and regulation of gene expression. Histones can be released after tissue injuries, and the extracellular histones cause cellular damage and organ dysfunction. Regardless of their clinical significance, the role and relevance of histones in ocular diseases are unknown. We studied the role of histones in eyes with retinal detachment (RD). Vitreous samples were collected during vitrectomy, and the concentration of histone H3 was measured by enzyme-linked immunosorbent assay. The location of the histones and related molecules was examined in a rat RD model. The release of histones and their effects on rat retinal progenitor cells R28 and ARPE-19 were evaluated in vitro. In addition, the protective role of the vitreous body against histones was tested. The intravitreal concentration of histones was higher in eyes with RD (mean, 30.9±9.8 ng/ml) than in control eyes (below the limit of detection, Po0.05). In the rat RD model, histone H3 was observed on the outer side of the detached retina and was associated with photoreceptor death. Histone H3 was released from cultured R28 by oxidative stress. Histones at a concentration 10 mg/ml induced the production of interleukin-8 in ARPE-19 cells (2.5-fold increase, Po0.05) that was mediated through the ERK1/2-and p38 MAPK-dependent pathways and Toll-like receptor 4. Histones were toxic to cells at concentrations of Z20 mg/ml. Vitreous body or hyaluronan decreased toxicity of histones by inhibiting diffusion of histones. These results indicate that histones are released from retinas with RD and may modulate the subretinal microenvironment by functioning as damage-associated molecular pattern molecules, thereby inducing proinflammatory cytokines or cell toxicity. In addition, the important role of the vitreous body and hyaluronan in protecting the retina from these toxic effects is suggested.

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“…After receptor activation, MAP kinase kinase kinase kinases (MAPKKKK) are activated, and phosphorylate downstream MAP kinase kinase kinases (MAPKKK; coloured green in Fig. 2), such as the Raf family [13].…”

Section: The Mapksmentioning

confidence: 99%

Mitogen activated protein kinases: a role in inflammatory bowel disease?

Broom

Widjaya

Troelsen

et al. 2009

Clinical and Experimental Immunology

154

114

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SummarySince their discovery more than 15 years ago, the mitogen activated protein kinases (MAPK) have been implicated in an ever-increasingly diverse array of pathways, including inflammatory signalling cascades. Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are characterized by the perpetual production of inflammatory mediators. Research into the transduction pathway behind this over-production has highlighted the potential mediating role for the MAPKs and their related signalling components. This review highlights some of the research into the role for the MAPKs and their related signalling proteins in influencing the progression of IBD.

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MAPKs and their relevance to arthritis and inflammation

Cited by 414 publications

References 97 publications

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Circulating fibrocytes contribute to the pathogenesis of collagen antibody–induced arthritis

Toxic effects of extracellular histones and their neutralization by vitreous in retinal detachment

Mitogen activated protein kinases: a role in inflammatory bowel disease?

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