IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Perlman, Harris; Bradley, Kathleen; Liu, Hongtao; Cole, Shawn M.; Shamiyeh, Eli; Smith, Roy C.; Walsh, Kenneth; Fiore, Stefano; Koch, Alisa E.; Firestein, Gary S.; Haines, G. Kenneth; Pope, Richard M.

doi:10.4049/jimmunol.170.2.838

Cited by 93 publications

(83 citation statements)

References 68 publications

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“…Nevertheless, it is clear that in our system p53 alone was not sufficient to activate programmed cell death. However, based on studies of collagen-induced arthritis, overexpression of p53 might be beneficial in RA through the induction of p21, even if PUMA is not induced (15).…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Cha¹,

Rosengren²,

Boyle³

et al. 2006

Arthritis & Rheumatism

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“…Before decalcification, ankles were examined for bone destruction using microcomputed tomography at Washington University School of Medicine. The other ankle was placed in liquid nitrogen, ground into a fine powder by mortal and pestle, digested in protein lysis buffer, and homogenized on ice for 20 s (3,31,32).…”

Section: Serum Transfer-induced Arthritismentioning

confidence: 99%

Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo

Brown

Hutcheson

Bickel

et al. 2004

The Journal of Immunology

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Over 1 billion monocytes are produced daily, with a small percentage differentiating into macrophages, suggesting that excess monocytes are deleted through a tightly regulated process. Although the in vivo mechanism governing monocyte/macrophage homeostasis is unknown, deletion of monocytes in culture is mediated by the Fas death pathway and is blocked by M-CSF. To determine the in vivo significance of Fas in monocyte development, mice lacking Fas (lpr/lpr) and mice deficient in Fas and M-CSF were examined. Compared with congenic control C57BL/6 (B6) mice, lpr/lpr mice displayed increased numbers of circulating monocytes. The lack of Fas in M-CSF-deficient mice resulted in an enhanced percentage, but not total numbers, of monocytes. Fas deficiency led to an increase in myeloid bone marrow progenitor potential only in M-CSF-intact mice. Although lpr/lpr and B6 mice had similar numbers of tissue macrophages, the loss of Fas in M-CSF-deficient mice was sufficient to increase the number of macrophages in a subset of tissues. Additionally, after stimulation with thioglycolate, lpr/lpr and B6 mice showed equivalent numbers of peritoneal macrophages. However, Fas-deficient peritoneal macrophages displayed a marked increase in spontaneous and LPS-induced proinflammatory molecule production. Moreover, Fas-deficient mice showed enhanced systemic inflammatory arthritis associated with up-regulation of IL-1β and CCL2 secretion, elevated numbers of inflammatory monocytes, and increased numbers of tissue macrophages. Collectively, these data suggest that Fas may be required for maintaining circulating monocytes and for suppressing macrophage activation and recruitment that are stimulus dependent.

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“…In the current study, FK228 exerted inhibitory effects not only on cell proliferation, but also on the in vivo expression of TNF␣ and IL-1␤ in synovial tissues. The inhibitory effect on cytokine expression might be partly related to the up-regulation of p21 WAF1/Cip1 , the overexpression of which was recently reported to reduce the amplification of inflammatory pathways by cytokines in RASFs (40,54). Further studies are required to identify precisely all of the genes that are up-regulated and down-regulated in RASFs by HDA inhibitors.…”

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confidence: 99%

“…INK4a did not correlate with the detection of apoptosis in human synovial membrane (43), and in vitro, p21 WAF1/Cip1 or p16 INK4a gene transfer of RASFs inhibited the cell cycle without having any effect on apoptosis (12,40). It is known that the progressive accumulation of p16…”

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confidence: 99%

Histone deacetylase inhibitor suppression of autoantibody‐mediated arthritis in mice via regulation of p16^INK4a and p21^WAF1/Cip1 expression

Nishida¹,

Komiyama²,

Miyazawa³

et al. 2004

Arthritis & Rheumatism

213

175

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Objective. To examine whether depsipeptide (FK228), a histone deacetylase (HDA) inhibitor, has inhibitory effects on the proliferation of synovial fibroblasts from rheumatoid arthritis (RA) patients, and to examine the effects of systemic administration of FK228 in an animal model of arthritis.Methods. Autoantibody-mediated arthritis (AMA) was induced in 19 male DBA/1 mice (6-7 weeks old); 10 of them were treated by intravenous administration of FK228 (2.5 mg/kg), and 9 were used as controls. The effects of FK228 were examined by radiographic, histologic, and immunohistochemical analyses and arthritis scores. RA synovial fibroblasts (RASFs) were obtained at the time of joint replacement surgery. In vitro effects of FK228 on cell proliferation were assessed by MTT assay. Cell morphology was examined by light and transmission electron microscopy. The effects on the expression of the cell cycle regulators p16INK4a and p21 WAF1/Cip1 were examined by real-time polymerase chain reaction and Western blot analysis. The acetylation status of the promoter regions of p16INK4a and p21 WAF1/Cip1 were determined by chromatin immunoprecipitation assay.Results. A single intravenous injection of FK228 (2.5 mg/ml) successfully inhibited joint swelling, synovial inflammation, and subsequent bone and cartilage destruction in mice with AMA. FK228 treatment induced histone hyperacetylation in the synovial cells and decreased the levels of tumor necrosis factor ␣ and interleukin-1␤ in the synovial tissues of mice with AMA. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by synovial hyperplasia, with excessive inflammatory cell infiltration in the joints, leading to erosion of the articular cartilage and marginal bone, with subsequent joint destruction (1). Despite an explosion of information over the last 2 decades, a detailed understanding of the mechanisms of synovial hyperplasia and inflammation is lacking. Recent reports have implicated rapid proliferation of synovial cells, overexpression of inflammatory genes, and impairment of apoptosis, which can allow the persistence of abnormal cells (2-4), in the disease process.Cyclin-dependent kinases (CDKs) are essential Dr.

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IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Cited by 93 publications

References 68 publications

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo

Histone deacetylase inhibitor suppression of autoantibody‐mediated arthritis in mice via regulation of p16^INK4a and p21^WAF1/Cip1 expression

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IL-6 and Matrix Metalloproteinase-1 Are Regulated by the Cyclin-Dependent Kinase Inhibitor p21 in Synovial Fibroblasts

Cited by 93 publications

References 68 publications

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

PUMA regulation and proapoptotic effects in fibroblast‐like synoviocytes

Fas Death Receptor Signaling Represses Monocyte Numbers and Macrophage Activation In Vivo

Histone deacetylase inhibitor suppression of autoantibody‐mediated arthritis in mice via regulation of p16INK4a and p21WAF1/Cip1 expression

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Histone deacetylase inhibitor suppression of autoantibody‐mediated arthritis in mice via regulation of p16^INK4a and p21^WAF1/Cip1 expression