Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Hammaker, Deepa; Boyle, David L.; Firestein, Gary S.

doi:10.4049/jimmunol.174.7.4301

Cited by 70 publications

(60 citation statements)

References 40 publications

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“…The studies were approved by the University of California, San Diego, Human Subjects Research Protection Program. FLS used for experiments were prepared from enzymatically dispersed synovial tissue, as described previously (7). Normal human skin fibroblasts were purchased from Cell Applications (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

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PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Cha¹,

Rosengren²,

Boyle³

et al. 2006

Arthritis & Rheumatism

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Objective. Although p53 is overexpressed in rheumatoid arthritis (RA) synovial tissue (ST), few synoviocytes undergo apoptosis. This could be partly due to low expression of proapoptotic genes. Deficient p53 upregulated modulator of apoptosis (PUMA), which is a major effector of p53-mediated cell death, could contribute to this phenomenon. To evaluate a method to induce apoptosis, the expression and function of PUMA was investigated in ST and cultured fibroblast-like synoviocytes (FLS).Methods. PUMA expression in ST was measured by immunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction analysis. Ad-p53 and plasmids encoding hemagglutinin-tagged, fulllength PUMA expression vector (HA-PUMA), PUMA lacking the Bcl-2 homology 3 domain, or pCEP4 were used to transfect FLS. Apoptosis was quantified by trypan blue exclusion, DNA fragmentation, and caspase 3 activation.Results. PUMA protein was detected in RA ST, although most of the immunoreactive protein was localized to sublining cells rather than the intimal lining synoviocytes. Western blot analysis showed no difference between RA ST and osteoarthritis (OA) ST. PUMA messenger RNA was detected in RA and OA ST, although the amounts were markedly lower than in the spleen and FLS. To determine if PUMA was inducible, FLS were transduced with Ad-p53. Even though p53 protein was produced and p21 expression was increased, PUMA expression was not enhanced. Consistent with this observation, Ad-p53 did not induce apoptosis in FLS. However, HA-PUMA transfection into FLS resulted in rapid apoptosis with the activation of caspase 3.Conclusion. PUMA can induce apoptosis by FLS and represents a potential target in RA.

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Section: Methodsmentioning

confidence: 99%

“…An empty plasmid vector (pCEP4; Invitrogen, Carlsbad, CA) was used as a negative control. FLS transfection was performed using the Amaxa human dermal fibroblast nucleofector kit (NHDF-adult; Amaxa Biosystems, Gaithersburg, MD), as described previously (7).…”

mentioning

confidence: 99%

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Cha¹,

Rosengren²,

Boyle³

et al. 2006

Arthritis & Rheumatism

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“…FLS were used from passages 3 through 9, during which time they are a homogeneous population of cells (,1% CD11b positive, ,1% phagocytic, and ,1% FcgRII and FcgRIII receptor positive). The detailed characterization and phenotyping of FLS were previously described (15)(16)(17)(18)(19). FLS were cultured and used at 80% confluence.…”

Section: Preparation Of Human Synovial Tissue and Flsmentioning

confidence: 99%

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

Bartók

Hammaker

Firestein

2014

The Journal of Immunology

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Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA. PI3Kδ isoform was recently identified as a key regulator of FLS growth and survival, suggesting that it could contribute to synoviocyte aggressive behavior. Therefore, we assessed the role of PI3Kδ in RA synoviocyte migration and invasion. We observed that PI3Kδ inhibition or small interfering RNA knockdown decreased platelet-derived growth factor (PDGF)–mediated migration and invasion of FLS. We then showed that PI3Kδ regulates the organization of actin cytoskeleton and lamellipodium formation during PDGF stimulation. To gain insight into molecular mechanisms, we examined the effect of PI3Kδ inhibition on Rac1/PAK, FAK, and JNK activation. Our studies suggest that Rac1/PAK is key target of PDGF-mediated PI3Kδ signaling, whereas FAK and JNK are not involved. Thus, PI3Kδ contributes to multiple aspects of the pathogenic FLS behavior in RA. These observations, together with previous findings that PI3Kδ regulates FLS growth and survival, suggest that PI3Kδ inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion.

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“…Preferential activation of upstream MKK3 or MKK6 leading to p38MAPK activation in synovial fibroblasts has also been described [122,123]. Deletion of p38β does not affect experimental arthritis, whereas deletion of the Mapk14 (p38α) confers protection against inflammatory bone loss.…”

Section: P38 Mapk Pathway In Rheumatoid Arthritismentioning

confidence: 99%

The Role of p38 MAPK in Rheumatic Diseases

Mavropoulos¹,

Κουτσουμπασ²,

Bogdanos³

2015

ITI

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Abstract-p38 mitogen activated protein kinase (p38 MAPK) signaling appears to play a significant role in the regulation of immune-mediated inflammatory responses and therefore has been linked with several autoimmune diseases. This review discusses the current data regarding the involvement of p38 MAP in rheumatic diseases characterized by arthritis, with special attention in psoriatic arthritis, an arthritis with no apparent autoimmune features, and rheumatoid arthritis, an arthritis with apparent autoimmune features.

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Regulation of p38 MAPK by MAPK Kinases 3 and 6 in Fibroblast-Like Synoviocytes

Cited by 70 publications

References 40 publications

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Phosphoinositide 3-Kinase δ Regulates Migration and Invasion of Synoviocytes in Rheumatoid Arthritis

The Role of p38 MAPK in Rheumatic Diseases

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