Fas‐mediated upregulation of vascular endothelial growth factor and monocyte chemoattractant protein‐1 expression in cultured dermal fibroblasts: Role in the inflammatory response

Liu

The Journal of Immunology

et al. 2009

115

Fas/FasL system has been extensively investigated with respect to its capacity to induce cellular apoptosis. However, accumulated evidences show that Fas signaling also exhibits nonapoptotic functions, such as induction of cell proliferation and differentiation. Lung cancer is one of cancer’s refractory to the immunotherapy, however, the underlying mechanisms remain to be fully understood. In this study, we show that Fas overexpression does not affect in vitro growth of 3LL cells, but promotes lung cancer growth in vivo. However, such tumor-promoting effect is not observed in FasL-deficient (gld) mice, and also not observed in the immune competent mice once inoculation with domain-negative Fas-overexpressing 3LL cells, suggesting the critical role of Fas signal in the promotion of lung cancer growth in vivo. More accumulation of myeloid-derived suppressor cells (MDSC) and Foxp3+ regulatory T cells is found in tumors formed by inoculation with Fas-overexpressing 3LL cells, but not domain-negative Fas-overexpressing 3LL cells. Accordingly, Fas-ligated 3LL lung cancer cells can chemoattract more MDSC but not regulatory T cells in vitro. Furthermore, Fas ligation induces 3LL lung cancer cells to produce proinflammatory factor PGE2 by activating p38 pathway, and in turn, 3LL cells-derived PGE2 contribute to the Fas ligation-induced MDSC chemoattraction. Furthermore, in vivo administration of cyclooxygenase-2 inhibitor can significantly reduce MDSC accumulation in the Fas-overexpressing tumor. Therefore, our results demonstrate that Fas signal can promote lung cancer growth by recruiting MDSC via cancer cell-derived PGE2, thus providing new mechanistic explanation for the role of inflammation in cancer progression and immune escape.

Section: Pge 2 Derived From the Fas-ligated Lung Cancer Cells Contribmentioning

confidence: 78%

Fas Signal Promotes Lung Cancer Growth by Recruiting Myeloid-Derived Suppressor Cells via Cancer Cell-Derived PGE2

Liu

The Journal of Immunology

et al. 2009

115

“…Although we could not completely eliminate the possibility that inflammatory cells induce Fas/FasL-mediated hepatocellular apoptosis, we would like to conclude that particularly fratricidal death by Fas-FasL interactions of neighbouring hepatocytes may actively contribute to ALF. Recently, it was shown that Fas ligation not only promotes apoptosis but also stimulates proinflammatory events such as macrophage infiltration and leukocyte recruitment during liver injury [37]. Leukocyte infiltration has been shown to be not only the cause, but also the consequence of hepatocyte apoptosis [38].…”

Section: Methodological Considerationsmentioning

confidence: 99%

Hepatocellular apoptosis is mediated by TNFα-dependent Fas/FasLigand cytotoxicity in a murine model of acute liver failure

et al. 2008

There is increasing evidence that the active contribution of hepatocytes to liver disease is strongly dependent on local cytokine environment. It has been shown in vitro that TNFalpha can enhance hepatocyte FasLigand (FasL)-mediated cytotoxicity. Here, we demonstrate that TNFalpha-induced apoptosis was associated with Fas and FasL upregulation and that a FasL-neutralizing antibody prevented TNFalpha-induced apoptosis. We further examined in vivo the relevance of the Fas/FasL pathway to hepatocellular apoptosis in a TNFalpha-driven model of acute liver failure. Livers of galactosamine/lipopolysaccharide (Gal/LPS)-exposed Fas wild-type mice highly expressed both Fas and FasL and revealed marked hepatocellular apoptosis that was almost completely blocked by soluble TNFalpha-receptor; this was also almost absent in Gal/LPS-exposed Fas lymphoproliferation mutant mice. Our data provide evidence for a direct link between TNFalpha and Fas/FasL in mediating hepatocyte apoptosis. Fratricidal death by Fas-FasL interactions of neighbouring hepatocytes may actively contribute to acute liver failure.

“…However, the Fas/FasL system is being increasingly recognized for its ability to trigger inflammation [ 29 ]. Numerous studies have demonstrated that activation of Fas signaling in a variety of non-lymphoid cells, including colonic and lung epithelial cells [ 33 , 34 ], hepatocytes [ 35 ], synoviocytes [ 36 ], macrophages [ 20 ], and fibroblasts [ 37 ], can lead to the expression and release of inflammatory factors in vitro and in vivo, in particular, at the early stage of inflammation development. Such factors may, in turn, recruit inflammatory cells, exacerbating the inflammatory process.…”

Section: Discussionmentioning

confidence: 99%

HMGB1 release triggered by the interaction of live retinal cells and uveitogenic T cells is Fas/FasL activation-dependent

Jiang

Wang

Yun

et al. 2015

J Neuroinflammation

BackgroundIt is not clear how invading autoreactive T cells initiate the pathogenic process inside the diseased organ in T cell-mediated organ-specific autoimmune disease. In experimental autoimmune uveitis (EAU) induced by adoptive transfer of interphotoreceptor retinoid-binding protein (IRBP)-specific T cells in mice, we have previously reported that intraocular inflammation was initiated by infiltrating IRBP-specific T cells that directly interacted with retinal cells and resulted in the active release of high mobility group box 1 (HMGB1), an important member of damage associate molecular patterns (DAMPs). Furthermore, blockade of HMGB1 in our murine model reduced intraocular inflammation via suppression of IRBP-specific T cell functions. These results have demonstrated that HMGB1 is an early and critical mediator of induction of intraocular inflammation. The present study identified the cell surface molecule that triggers HMGB1 secretion.MethodsRetinal explants from Fas-deficient (Faslpr) and wild-type (Wt) C57BL/6 (B6) mice were cultured with activated IRBP 1–20 peptide-specific T cells or with a Fas-activating antibody (Jo2), and then the level of HMGB1 in culture supernatants were detected by ELISA. In addition, released HMGB1 was examined in the eye of Faslpr and Wt mice after IRBP-specific T cell transfer. Uveitis was evaluated in the IRBP-specific T cell transferred Faslpr mice after recombinant HMGB1 was restored within the eye and in the IRBP-specific T cell transferred Wt mice after they were treated with a Fas antagonist (Met12).ResultsIn contrast to retinal explants from Wt mice, those from Faslpr mice did not release HMGB1 after exposure to IRBP-specific T cells or to Jo2. The release of HMGB1 by Wt retinal explants was suppressed by Met 12. Moreover, after IRBP-specific T cell injection, Faslpr mice did not release HMGB1 in the eye or develop EAU, but intravitreous injection of HMGB1 resulted in intraocular inflammation. Finally, tEAU in Wt mice was attenuated by local treatment with Met 12. Unlike HMGB1, Fas-induced IL-1 and IL-18 were not essential for tEAU induction.ConclusionOur results show that interaction of retinal cells with infiltrating uveitogenic T cells leads to rapid release of HMGB1 via the Fas/FasL inflammatory signaling pathway.