Antibody Binding to Fas Ligand Attenuates Inflammatory Cell Infiltration and Cytokine Secretion, Leading to Reduction of Myocardial Infarct Areas and Reperfusion Injury

Shiraishi, Hiroaki; Toyozaki, Tetsuya; Tsukamoto, Yoshiaki; Saito, Toshihiro; Masuda, Yoshiaki; Hiroshima, Kenzo; Ohwada, Hayato; Kobayashi, Nobuyuki; Hiroe, Michiaki

doi:10.1097/01.lab.0000029148.88524.ce

Cited by 18 publications

(10 citation statements)

References 40 publications

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“…21 Moreover, FasL cross-linking leads to recruitment of neutrophils and increased inflammation, 12 and FasL deficiency attenuates inflammatory cell infiltration and cytokine secretion. 11,22 However, overexpression of FasL in dendritic cells decreased allergen-specific T cells and airway inflammation. 15,25 Studies on the effects of FasL in IRI have also produced conflicting results.…”

Section: Discussionmentioning

confidence: 99%

“…15,25 Studies on the effects of FasL in IRI have also produced conflicting results. [22][23][24][25] FasL expression was increased in infiltrating neutrophils and T lymphocytes after renal IRI; 28 however, little is known about their role in AKI after IRI.…”

Section: Discussionmentioning

confidence: 99%

“…20,21 T lymphocytes are important mediators of IRI of kidney and other organs, and FasL could have a role in IRI through modulation of T cells homeostasis. Although various effects of FasL on IRI have been reported, [22][23][24][25] little is known about the role of FasL in renal IRI, particularly from the angle of leukocytes.…”

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confidence: 99%

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Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Jang

Huang

et al. 2011

Journal of the American Society of Nephrology

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Inflammation contributes to the pathogenesis of ischemic acute kidney injury (AKI), and T cells mediate the early phase of ischemia-reperfusion injury (IRI). The Fas/Fas ligand (FasL) pathway modulates the balance of T cell subsets in the peripheral circulation as well as multiple inflammatory responses, suggesting that FasL may mediate ischemic AKI. Here, we induced bilateral renal IRI in mice bearing a loss-of-function mutation of FasL (the gld mutation) and in wild-type mice. Compared with wild-type mice, serum creatinine was lower in gld mice (1.4 Ϯ 0.9 mg/dl versus 2.6 Ϯ 0.4) at 24 hours after IRI (P Ͻ 0.05). In addition, gld mice had fewer TNF-␣-producing T lymphocytes in the kidneys and renal lymph nodes. Furthermore, pharmacologic blockade of FasL protected the kidneys of wild-type mice from IRI. Analysis of bone marrow chimeric mice suggested that the pathogenic effect of FasL involves leukocytes; reconstitution of wild-type mice with gld splenocytes attenuated IRI. In contrast, reconstitution of gld mice with wild-type splenocytes enhanced IRI. These data demonstrate that FasL, particularly on leukocytes, mediates ischemic AKI.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Blocking Fas Ligand on Leukocytes Attenuates Kidney Ischemia-Reperfusion Injury

Jang

Huang

et al. 2011

Journal of the American Society of Nephrology

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“…Although Fas is best known for its involvement in the regulation of apoptosis, Fas ligation also contributes to activation of NF-B (Ponton et al, 1996), and it has been shown that interruption of Fas/FasL signaling suppressed NF-B activation and cytokine expression (Shiraishi et al, 2002). We recently showed that NF-B activation and production of proinflammatory cytokines were suppressed in sFas transgenic mice (Niu et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Cardiac-Targeted Expression of Soluble Fas Attenuates Doxorubicin-Induced Cardiotoxicity in Mice

Niu¹,

Azfer

Wang³

et al. 2008

J Pharmacol Exp Ther

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Doxorubicin (Dox) is known to cause cardiomyopathy and congestive heart failure upon chronic administration. The mechanisms underlying these toxicities remain uncertain but have been attributed, at least in part, by induction of cardiac cell apoptosis. Fas ligation with its cognate ligand (FasL) induces apoptosis and activates cellular inflammatory responses associated with tissue injury. We determined whether interruption of Fas/FasL interaction by cardiac-targeted expression of soluble Fas (sFas), a competitive inhibitor of FasL, would protect against Dox chronic cardiotoxicity in mice. Wild-type (WT) and sFas transgenic mice were administrated intravenously with 4 mg/kg Dox or with an equivalent volume of saline twice a week for a total of 10 injections. There were 25% mortality in WT mice, but no death was observed in sFas mice during the period of Dox treatment. Echocardiographic evaluation revealed a significant decrease in left ventricle fractional shortening after Dox treatment in WT mice but not in sFas mice. WT mice treated with Dox developed extensive myocardial cytoplasmic vacuolization, apoptosis, and interstitial fibrosis, which were much less or absent in sFas mice. The increased inducible nitric oxide synthase expression, nitric oxide production, superoxide generation, and peroxynitrite formation after Dox treatment in WT mice were attenuated by sFas expression. sFas expression also attenuated Dox-mediated induction of proinflammatory cytokines, tumor necrosis factor-␣, interleukin (IL)-1␤, and IL-6 in the myocardium. These observations indicate that FasL is an important mediator in Dox-associated cardiotoxicity by generating reactive oxygen and nitrogen species.

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“…[32][33][34][35][36][37][38][39][40][41] Although not fully established, factors evident in atherosclerotic lesions can influence the expression of these death receptors and their ligands (Table 2), and some of these factors include TNF-␣ itself, insulin, oxLDL, IFN family members, homocystein, IL-1, and NFB. Increased or decreased expression of TNFR or TNF ligands may contribute to their physiological role to induce death or survival of cells; however, vascular cells are frequently resistant to TNFRmediated death.…”

Section: Role Of Death Receptors In the Vasculaturementioning

confidence: 99%