The Tyrosine Kinase Inhibitor Tyrphostin AG126 Reduces the Development of Acute and Chronic Inflammation

Cuzzocrea, Salvatore; McDonald, Michelle C.; Mazzon, Emanuela; Siriwardena, Dilani; Calabró, Giusi; Britti, Domenico; Mazzullo, G.; Sarro, Angela De; Caputi, Achille P.; Thiemermann, Christoph

doi:10.1016/s0002-9440(10)64526-9

Cited by 23 publications

(22 citation statements)

References 51 publications

(40 reference statements)

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“…Because the activation of several PLA 2 isoforms can be influenced by phosphorylation (19), it is conceivable that AG-126 may inhibit a kinase that couples K ϩ efflux to iPLA 2 activation. The molecular target of AG-126 is likely to be important for the inflammatory role of the P2X 7 R, because treating mice with AG-126 is able to prevent anti-collagen-induced arthritis, a disease model in which the P2X 7 R has also been implicated (8,20).…”

Section: Discussionmentioning

confidence: 99%

“…To further investigate how brief P2X 7 R activation of intact macrophages induces accelerated caspase-1 and IL-1␤ processing in cell-free lysates, we tested whether any common signaling components might be required for the basal activation of caspase-1 processing by hypotonic lysis and the acceleration of caspase-1 processing after P2X 7 R stimulation. Previous studies have reported that AG-126, a tyrphostin family tyrosine kinase inhibitor, can block inflammatory responses in vivo as well as ATP-mediated caspase-1 activation and secretion of IL-1␤ and IL-18 from human monocytes (8,25). The specific target of AG-126 is unknown.…”

Section: Stimulation Of K ϩ Loss From Intact Cells Is Necessary For Imentioning

confidence: 99%

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Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

Kahlenberg

Dubyak

2004

American Journal of Physiology-Cell Physiology

311

272

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The mechanisms underlying caspase-1 activation and IL-1␤ processing during inflammatory activation of monocytes and macrophages are not well defined. Here, we describe an in vitro proteolytic processing assay that allows for comparison of caspase-1 regulatory components in a cell-free system separately from the confounding issue of IL-1␤ secretion. Analysis of in vitro IL-1␤ and caspase-1 processing in lysates from unstimulated Bac1 murine macrophages indicated a slow rate of basal caspase-1 activation and proteolytic maturation of IL-1␤. In contrast, brief (5 min) treatment of intact macrophages with extracellular ATP (as an activator of the P2X7 receptor) or nigericin before cell lysis markedly accelerated the in vitro processing of caspase-1 and IL-1␤. This acceleration of in vitro processing was strictly dependent on loss of intracellular K ϩ from the intact cells. The induction of in vitro caspase-1 activation by lysis per se or by K ϩ loss before lysis was sensitive to pretreatment of intact macrophages with the tyrphostin AG-126 or bromoenol lactone, an inhibitor of Ca 2ϩ -independent phospholipase A2. Caspase-1 activation and IL-1␤ processing in lysates from unstimulated macrophages were also accelerated by addition of recombinant ASC, a previously identified adapter protein that directly associates with caspase-1. These data indicate that increased K ϩ efflux via P2X7 nucleotide receptor stimulation activates AG-126-and bromoenol lactone-sensitive signaling pathways in murine macrophages that result in stably maintained signals for caspase-1 regulation in cell-free assays.AG-126; ASC; bromoenol lactone; IL-1␤; inflammation (IL-1␤) is an important proinflammatory cytokine with circulating levels that are tightly regulated to prevent aberrant activation of pathways that can lead to chronic inflammation, septic shock, or death (9). IL-1␤ accumulates as a 33-kDa procytokine (proIL-1␤) in the cytoplasm of monocytes and macrophages, and its activation depends on cleavage to the active, mature 17-kDa form (mIL-1␤) by the enzyme caspase-1 (32, 44). Caspase-1 is synthesized as a low-activity 45-kDa zymogen (procaspase-1) that is proteolytically activated by cleavage of its COOH terminus into p10 and p20 subunits. These p10 and p20 subunits assemble to form a tetramer, a homodimer of heterodimers, that is highly active in its ability to cleave and activate proIL-1␤ (45). In vitro and overexpression studies have suggested that the activation of procaspase-1 depends on the oligomerization of two or more procaspase-1 molecules via caspase association recruitment domain (CARD) interactions between proteins able to bind to the CARD domain of procaspase-1 (12,31,35,36,40,46). Martinon et al. (24) recently reported that a four-protein complex, termed the inflammasome, can form in vitro and result in caspase-1 activation. Intermolecular procaspase-1 autocatalytic cleavage is then believed to generate the highly active caspase-1 tetramers (45). However, the intracellular signaling pathways that mediate the activation o...

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Section: Discussionmentioning

confidence: 99%

Section: Stimulation Of K ϩ Loss From Intact Cells Is Necessary For Imentioning

confidence: 99%

Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

Kahlenberg

Dubyak

2004

American Journal of Physiology-Cell Physiology

311

272

View full text Add to dashboard Cite

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“…We also used kringles 1-5, a proteolytic cleavage fragment of endogenous plasminogen protein, as a therapy targeting angiogenesis in CIA (20). In animal models of arthritis in mice and rats, as well as in an acute inflammatory recruitment air pouch model, blocking of angiogenesis by targeting the tyrosine kinase activity of VEGFR has been demonstrated (46); in addition, tyrosine kinase inhibition by other synthetic compounds in autoimmune arthritis and chronic inflammatory conditions has been described (47). Engagement of HER receptors has been known to increase the release of the proangiogenic factor VEGF in cancers (48,49).…”

Section: Discussionmentioning

confidence: 99%

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

Sumariwalla¹,

Pei²,

Zhang³

et al. 2008

Arthritis & Rheumatism

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Objective. To evaluate the therapeutic potential of the human epidermal growth factor receptor (HER) family inhibitor, herstatin, in an animal model of arthritis.Methods. Constructs of herstatin and modified tissue plasminogen activator (tPA)-herstatin were expressed in HEK 293T cells, and secreted protein was analyzed by Western blotting. Tissue PA-herstatin adenovirus (Ad-tPA-Her) was prepared, and titers established. Gene expression of Ad-tPA-Her was determined by polymerase chain reaction using HeLa cells. Pharmacokinetics of gene and protein expression in vivo in liver tissue and serum samples were confirmed via intravenous administration of Ad-tPA-Her. Clinical signs of disease were monitored in arthritic DBA/1 mice after therapeutic administration of Ad-tPA-Her, and histologic analysis of hind foot specimens was performed.Results. Native herstatin was not secreted in supernatants, while modified tPA-herstatin was detected in abundance. HeLa cells stably expressed the tPA-herstatin gene when infected with virus. Additionally, tPA-herstatin gene and protein expression was observed over time in mice treated with virus. Importantly, Ad-tPA-Her, when administered therapeutically to arthritic mice, controlled clinical and histologic signs of disease and reduced the number of joints with severe damage.Conclusion. Our results support the notion that the human epidermal growth factor receptor family has a role in the progression of collagen-induced arthritis. The novel tPA-herstatin fusion protein could be used as an effective therapeutic tool for control of inflammatory disorders involving an angiogenic component.

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“…Before injection, CII was emulsified with an equal volume of CFA. CIA was induced as described previously (Szabó et al, 1998;Cuzzocrea et al, 2000b). On day 1, mice were injected intradermally at the base of the tail with 100 l of the emulsion (containing 100 g of CII).…”

Section: Methodsmentioning

confidence: 99%

The Cyclopentenone Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂Attenuates the Development of Acute and Chronic Inflammation

et al. 2002

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Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of ligandactivated transcription factors that are related to retinoid, steroid, and thyroid hormone receptors. The PPAR-␥ receptor subtype seems to play a pivotal role in the regulation of cellular proliferation and inflammation. Recent evidence also suggests that the cyclopentenone prostaglandin (PG) 15-deoxy-⌬ 12,14 -PGJ 2 (15d-PGJ 2 ), which is a metabolite of prostaglandin D 2 , functions as an endogenous ligand for PPAR-␥. We postulated that 15d-PGJ 2 would attenuate inflammation. In the present study, we have investigated the effects of 15d-PGJ 2 of acute and chronic inflammation (carrageenan-induced pleurisy and collagen-induced arthritis, respectively) in animal models. We report for the first time, to our knowledge, that 15d-PGJ 2 (given at 10, 30, or 100 g/kg i.p. in the pleurisy model or at 30 g/kg i.p every 48 h in the arthritis model) exerts potent antiinflammatory effects (e.g., inhibition of pleural exudate formation, mononuclear cell infiltration, delayed development of clinical indicators, and histological injury) in vivo. Furthermore, 15d-PGJ 2 reduced the increase in the staining (immunohistochemistry) for nitrotyrosine and poly (ADP-ribose) polymerase and the expression of inducible nitric-oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated mice and in the joints from collagen-treated mice. Thus, 15d-PGJ 2 reduces the development of acute and chronic inflammation. Therefore, the cyclopentenone prostaglandin 15d-PGJ 2 may be useful in the therapy of acute and chronic inflammation.

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The Tyrosine Kinase Inhibitor Tyrphostin AG126 Reduces the Development of Acute and Chronic Inflammation

Cited by 23 publications

References 51 publications

Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

The Cyclopentenone Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂Attenuates the Development of Acute and Chronic Inflammation

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The Tyrosine Kinase Inhibitor Tyrphostin AG126 Reduces the Development of Acute and Chronic Inflammation

Cited by 23 publications

References 51 publications

Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release

Mechanisms of caspase-1 activation by P2X7 receptor-mediated K+ release

Antagonism of the human epidermal growth factor receptor family controls disease severity in murine collagen‐induced arthritis

The Cyclopentenone Prostaglandin 15-Deoxy-Δ12,14-Prostaglandin J2Attenuates the Development of Acute and Chronic Inflammation

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Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

Mechanisms of caspase-1 activation by P2X₇ receptor-mediated K⁺ release

The Cyclopentenone Prostaglandin 15-Deoxy-Δ^12,14-Prostaglandin J₂Attenuates the Development of Acute and Chronic Inflammation