Neutrophils induce apoptosis of lung epithelial cells via release of soluble Fas ligand

Abstract

Neutrophils release soluble Fas ligand (sFasL), which can induce apoptosis in certain Fas-bearing cell types (Liles WC, Kiener PA, Ledbetter JA, Aruffo A, and Klebanoff SJ. J Exp Med 184: 429-440, 1996). We hypothesized that neutrophils could induce alveolar epithelial apoptosis via release of sFasL. A549 pulmonary adenocarcinoma cells expressed surface Fas and underwent cell death (10 +/- 7% viability) and DNA fragmentation (354 +/- 98% of control cells) when incubated with agonistic CD95/Fas monoclonal antibody (P < 0.05). Coincubation with human neutrophils induced significant A549 cell death at 48 (51 +/- 9% viability; P < 0.05) and 72 h (25 +/- 10%; P < 0.05) and increased DNA fragmentation (178 +/- 42% of control cells; P < 0.05), with morphological characteristics of apoptosis. The addition of antioxidants did not inhibit apoptosis. sFasL concentrations were maximally increased in coculture medium at 24 h (4.9 +/- 0.7 ng/ml; P < 0.05). Neutrophil-induced A549 cell apoptosis was blocked by inhibitory anti-Fas (42 +/- 6% of control cells; P < 0.05) and anti-FasL monoclonal antibodies (29 +/- 3%; P < 0.05). Human neutrophils and Fas similarly affected murine primary alveolar epithelial cell bilayers, and caspase activation occurred in response to Fas exposure. We conclude that neutrophils undergoing spontaneous apoptosis induce A549 cell death and DNA fragmentation, independent of the oxidative burst, that is mediated by sFasL.

The Antiproliferative Activity of Saponin-Enriched Fraction from Bupleurum Kaoi Is through Fas-Dependent Apoptotic Pathway in Human Non-small Cell Lung Cancer A549 Cells

“…Serrao et al have reported that neutrophils induce apoptosis of lung epithelial cells via release of soluble FasL. 24) Our study indicated that Fas ligands, mFasL and sFasL, increased in SEF-treated A549 cells. Moreover, the level of Fas/APO-1 and the activity of caspase-8 were simultaneously enhanced in FasL-upregulating A549 cells.…”

Signaling through Up-Regulated C3a Receptor Is Key to the Development of Experimental Lupus Nephritis

“…MRL/lpr mice lack Fas (3), a member of the TNFR family, and consequently have impaired apoptosis with expansion of autoreactive lymphocytes, although apoptosis can occur in these mice through alternatively available pathways. The complement system has relevance to apoptosis, both in the clearance of apoptotic cells (8,53) and in its potential to lead to apoptosis, such as via direct effects of C5a (54) or C5b-9 (55-57) or by recruiting inflammatory cells that can themselves induce apoptosis (58,59). A clear role for apoptosis has been shown in a variety of acute renal diseases (53, 56, 60 -62), as well as in the changes that evolve more chronically in lupus nephritis (63,64).…”

The pathogenesis of and susceptibility to malabsorption syndrome in broilers is associated with heterophil influx into the intestinal mucosa and epithelial apoptosis

“…Heterophils (PMNL) might produce tumour necrosis factor-a and nitric oxide, followed by induction of apoptosis (Buttke & Sandstorm, 1994;Le'Negrate et al ., 2000;Choi & Chae, 2002). Release of soluble Fas-ligand by PMNL can trigger apoptosis in lung epithelial cells (Serrao et al ., 2001). Another explanation for crypt apoptosis is that specific components in the MAS inoculum might directly trigger epithelial apoptosis.…”