Molecular Targets of Rheumatoid Arthritis

Okamoto, Hiroshi; Hoshi, Daisuke; Kiire, Akiko; Yamanaka, Hisashi; Kamatani, Naoyuki

doi:10.2174/187152808784165199

Cited by 64 publications

(45 citation statements)

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“…Circulating IL-8, on the other hand, has previously been detected only in SCD patients when in crisis or presenting acute syndrome [16 -19]; the current availability of more sensitive detection tools, however, probably explains this discrepancy. A role for TNF-␣, an important proinflammatory cytokine, has been appointed in a number of inflammatory diseases that include sepsis, rheumatoid arthritis, and Chrohn's disease, where this molecule appears to participate in up-regulating the cytokine cascades responsible for inflammation [20,21]. IL-8 (CXCL8) is a key mediator in neutrophil-mediated acute inflammation, with a crucial role in a number of chronic inflammatory diseases and lung pathologies [22].…”

Section: Discussionmentioning

confidence: 99%

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

Lanaro

Franco‐Penteado

Albuqueque

et al. 2008

Journal of Leukocyte Biology

189

142

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Inflammation, cell adhesion to vascular endothelium, and endothelial injury contribute to sickle cell anemia (SCA) vaso-occlusion. Although alterations in inflammatory cytokines and biomarkers have been related, reports have been conflicting, and a conclusive role for these molecules in the disease remains to be established. Furthermore, the effect of hydroxyurea therapy (HU) on the release of inflammatory mediators is not understood. This study aimed to determine plasma levels and leukocyte gene expressions of inflammatory mediators in healthy controls, steady-state SCA patients, and SCA patients on HU therapy. TNF-␣, IL-8, and PGE 2 levels were significantly higher in the plasma of SCA individuals when compared with control individuals. HU therapy was associated with a significant reversal of aug-

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Section: Discussionmentioning

confidence: 99%

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

Lanaro

Franco‐Penteado

Albuqueque

et al. 2008

Journal of Leukocyte Biology

189

142

View full text Add to dashboard Cite

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“…SAA has been shown to bind to a variety of receptors including the formyl peptide-receptor like-1 receptor (80,81), Tanis (82), CD36 and lysosomal integral membrane protein-II analogous-1 (83), the receptor for advanced glycation end products (84,85), ␣IIb␤3 integrin (86), and the scavenger receptor BI (87,88). More recently, it was suggested that SAA-induced nitric oxide production by macrophages is Toll-like receptor (TLR) 4-dependent (89).…”

Section: Discussionmentioning

confidence: 99%

Secretory Phospholipase A2, Group IIA Is a Novel Serum Amyloid A Target Gene

Sullivan

Seidl

Rich

et al. 2010

Journal of Biological Chemistry

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Atherosclerosis is a multifactorial vascular disease characterized by formation of inflammatory lesions. Elevated circulating acute phase proteins indicate disease risk. Serum amyloid A (SAA) is one such marker but its function remains unclear. To determine the role of SAA on aortic smooth muscle cell gene expression, a preliminary screen of a number of genes was performed and a strong up-regulation of expression of secretory phospholipase A 2 , group IIA (sPLA 2 ) was identified. The SAAinduced increase in sPLA 2 was validated by real time PCR, Western blot analysis, and enzyme activity assays. Demonstrating that SAA increased expression of sPLA 2 heteronuclear RNA and that inhibiting transcription eliminated the effect of SAA on sPLA 2 mRNA suggested that the increase was transcriptional. Transient transfections and electrophoretic mobility shift assays identified CAAT enhancer-binding protein (C/EBP) and nuclear factor B (NFB) as key regulatory sites mediating the induction of sPLA 2 . Moreover, SAA activated the inhibitor of NF-B kinase (IKK) in cultured smooth muscle cells. Previous reports showed that interleukin (IL)-1␤ up-regulates Pla2g2a gene transcription via C/EBP␤ and NFB. Interestingly, SAA activated smooth muscle cell IL-1␤ mRNA expression, however, blocking IL-1 receptors had no effect on SAA-mediated activation of sPLA 2 expression. Thus, the observed changes in sPLA 2 expression were not secondary to SAA-induced IL-1 receptor activation. The association of SAA with high density lipoprotein abrogated the SAA-induced increase in sPLA 2 expression. These data suggest that during atherogenesis, SAA can amplify the involvement of smooth muscle cells in vascular inflammation and that this can lead to deposition of sPLA 2 and subsequent local changes in lipid homeostasis.Elevated circulating acute phase proteins correlate with an increased risk for atherosclerosis (1-4). One such disease indicator is serum amyloid A (SAA) 2 (5). The SAA protein family consists of 12-14-kDa constitutive (SAA 4 ) and acute phase (SAA 1 , SAA 2 , and SAA 3 ) isoforms. During inflammation, there are large changes in liver-derived plasma levels of the acute phase isoforms, SAA 1 and SAA 2 (6, 7). The other acute phase isoform, SAA 3 , is extrahepatically inducible (8), and although the locus equivalent to SAA 3 was previously believed to be a pseudogene in humans, Larson and co-workers (9) demonstrated its expression by mammary gland epithelial cells. Proinflammatory stimuli induce SAA expression in liver; optimal expression is achieved with a combination of interleukin (IL)-1 and IL-6 (10, 11). Extrahepatic synthesis of SAA by synovial fibroblasts, macrophages, adipocytes, and smooth muscle cells has been documented (12-15). SAA is also expressed in atherosclerotic lesions (13,16,17). Although several roles have been suggested, the functions of SAA remain uncertain (7). Our laboratory demonstrated that in response to IL-1␣, cultured aortic smooth muscle cells synthesize SAA (18) leading to the hypothesis that during ather...

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“…Evidence generated in both animal models and in human studies support the role of TNF-␣, IL-1, and IL-6 in the pathogenesis of RA (Dayer et al, 2001;Scott and Kingsley, 2006;Hennigan and Kavanaugh, 2008). Treatment with Remicade, Humira, Enbrel, Kineret, and Tocilizumab reduce joint pain and swelling, and retard progression of bone loss in patients whose disease is unsatisfactorily controlled by conventional disease-modifying antirheumatic drugs (Okamoto et al, 2008). However, these biologic agents are limited due to the requirement for parenteral administration, difficulty in dose titration, poor reversibility, induction of host neutralizing antibody response, high production costs, and a significant population of patient refractory to the treatment.…”

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confidence: 99%

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

Hope¹,

Anderson²,

Burnette³

et al. 2009

J Pharmacol Exp Ther

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Signal transduction through the p38 mitogen-activated protein (MAP) kinase pathway is central to the transcriptional and translational control of cytokine and inflammatory mediator production. p38 MAP kinase inhibition hence constitutes a promising therapeutic strategy for treatment of chronic inflammatory diseases, based upon its potential to inhibit key pathways driving the inflammatory and destructive processes in these debilitating diseases. The present study describes the pharmacological properties of the Nphenyl pyridinone p38 MAP kinase inhibitor benzamide [3-[3-bromo-4-[(2,4-PH-797804 is an ATP-competitive, readily reversible inhibitor of the ␣ isoform of human p38 MAP kinase, exhibiting a K i ϭ 5.8 nM. In human monocyte and synovial fibroblast cell systems, PH-797804 blocks inflammation-induced production of cytokines and proinflammatory mediators, such as prostaglandin E 2 , at concentrations that parallel inhibition of cell-associated p38 MAP kinase. After oral dosing, PH-797804 effectively inhibits acute inflammatory responses induced by systemically administered endotoxin in both rat and cynomolgus monkeys. Furthermore, PH-797804 demonstrates robust anti-inflammatory activity in chronic disease models, significantly reducing both joint inflammation and associated bone loss in streptococcal cell wall-induced arthritis in rats and mouse collagen-induced arthritis. Finally, PH-797804 reduced tumor necrosis factor-␣ and interleukin-6 production in clinical studies after endotoxin administration in a dose-dependent manner, paralleling inhibition of the target enzyme. Low-nanomolar biochemical enzyme inhibition potency correlated with p38 MAP kinase inhibition in human cells and in vivo studies. In addition, a direct correspondence between p38 MAP kinase inhibition and antiinflammatory activity was observed with PH-797804, thus providing confidence in dose projections for further human studies in chronic inflammatory disease.Rheumatoid arthritis (RA) is an aggressive autoimmune disease involving complex interactions among T cells, macrophages, synoviocytes, and other immune cells (Firestein, 2003). Analysis of synovial fluid and tissue from RA patients implicated key cytokines, including TNF-␣, IL-1␤, and IL-6 in the pathogenesis of the disease (Firestein et al., 1990). Further studies shed light on the complex networks within which these cytokines function and the delicate balance between a pro-or an anti-inflammatory outcome (McInnes and ABBREVIATIONS: RA, rheumatoid arthritis; TNF, tumor necrosis factor; IL, interleukin; COX, cyclooxygenase; MAP, mitogen-activated protein; ERK, extracellular signal-regulated kinase; JNK, c-Jun NH 2 -terminal kinase; benzamide,methoxy]-6-methyl-2-oxo-1(2H)-pyridinyl]-N,4-dimethyl-, (Ϫ)-(9CI); SCW, streptococcal cell wall; LPS, lipopolysaccharide; MKK, mitogen-activated protein kinase kinase; EGFRP, epidermal growth factor receptor peptide; GST, glutathione transferase; RASF, rheumatoid arthritis synovial fibroblast(s); MK-2, mitogen-activated protein kinase-act...

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Molecular Targets of Rheumatoid Arthritis

Cited by 64 publications

References 0 publications

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

Altered levels of cytokines and inflammatory mediators in plasma and leukocytes of sickle cell anemia patients and effects of hydroxyurea therapy

Secretory Phospholipase A2, Group IIA Is a Novel Serum Amyloid A Target Gene

Anti-Inflammatory Properties of a NovelN-Phenyl Pyridinone Inhibitor of p38 Mitogen-Activated Protein Kinase: Preclinical-to-Clinical Translation

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