DOI: 10.1189/jlb.0102006. Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity

Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity

10.1189/jlb.0102006

Crossref journal-article

Oxford University Press (OUP)

Journal of Leukocyte Biology (286)

Abstract

Abstract Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal’s or patient’s morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host’s ability to ward off a septic challenge.

Bibliography

Chung, C.-S., Song, G. Y., Lomas, J., Simms, H. H., Chaudry, I. H., & Ayala, A. (2003). Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity. Journal of Leukocyte Biology, 74(3), 344â351.

Authors 6

Chun-Shiang Chung (first)
Grace Y Song (additional)
Joanne Lomas (additional)
H Hank Simms (additional)
Irshad H Chaudry (additional)
Alfred Ayala (additional)

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Dates

Type	When
Created	22 years ago (Aug. 29, 2003, 4:50 p.m.)
Deposited	2 years, 5 months ago (March 30, 2023, 9:58 p.m.)
Indexed	4 days, 6 hours ago (Aug. 27, 2025, 12:05 p.m.)
Issued	22 years, 2 months ago (June 3, 2003)
Published	22 years, 2 months ago (June 3, 2003)
Published Online	22 years, 2 months ago (June 3, 2003)
Published Print	21 years, 11 months ago (Sept. 1, 2003)

Funders 1

National Institutes of Health 10.13039/100000002
Region: Americas
gov (National government)
Labels3
1. Institutos Nacionales de la Salud
2. US National Institutes of Health
3. NIH
Awards1
1. R01-GM53209

BibTeX

@article{Chung_2003, title={Inhibition of Fas/Fas ligand signaling improves septic survival: differential effects on macrophage apoptotic and functional capacity}, volume={74}, ISSN={1938-3673}, url={http://dx.doi.org/10.1189/jlb.0102006}, DOI={10.1189/jlb.0102006}, number={3}, journal={Journal of Leukocyte Biology}, publisher={Oxford University Press (OUP)}, author={Chung, Chun-Shiang and Song, Grace Y and Lomas, Joanne and Simms, H Hank and Chaudry, Irshad H and Ayala, Alfred}, year={2003}, month=jun, pages={344–351} }

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  "abstract": "<jats:title>Abstract</jats:title>\n               <jats:p>Signaling through the Fas/Fas ligand (FasL) pathway plays a central role in immune-cell response and function; however, under certain pathological conditions such as sepsis, it may contribute to the animal\u2019s or patient\u2019s morbidity and mortality. To determine the contribution of FasL to mortality, we conducted survival studies by blocking Fas/FasL with Fas receptor fusion protein (FasFP) in vivo. C3H/HeN mice received FasFP or the saline vehicle (veh) immediately (0 h) or delayed (12 h), after sepsis induced by cecal ligation and puncture (CLP). Subsequently, we examined the effect of FasFP treatment (12 h post-CLP) on macrophage apoptosis and functional capacities. Peritoneal and splenic macrophages and Kupffer cells from sham-veh-, CLP-veh-, sham-FasFP-, or CLP-FasFP-treated mice were harvested 24 h after CLP and stimulated with lipopolysaccharide (LPS) for 24 h. The results indicate that only delayed (12 h) but not 0 h administration of FasFP demonstrated a significant increase in survival. The ability of all macrophage populations to release interleukin (IL)-6 was significantly depressed, and IL-10 release was augmented after CLP. FasFP treatment attenuated the increased IL-10 release in Kupffer cells. However, althogh enhanced susceptibility to LPS-induced apoptosis could be suppressed in CLP mouse Kupffer cells by FasFP, FasFP did not change the peritoneal or splenic macrophage response. Furthermore, FasFP attenuated the elevated plasma levels of liver enzymes after sepsis. These data indicate that in vivo inhibition of Fas/FasL signaling has tissue-specific effects on the induction of macrophage apoptosis, functional changes, and liver damage, which may contribute to the host\u2019s ability to ward off a septic challenge.</jats:p>",
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