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* Division of Pulmonary and Critical Care Medicine,
Department of Medicine, and
Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, MD 21201;
Research Services, Baltimore Veterans Affairs Medical Center; Baltimore, MD 21201; and
¶ Critical Care Medicine Department, National Institutes of Health, Bethesda, MD 20892
Human neutrophilic polymorphonuclear leukocytes (PMNs) are central to innate immunity and are responsible for clearance of pathogens. PMNs undergo a tightly regulated apoptosis program that allows for timely clearance of PMNs without extravasation of toxic intracellular contents. We investigated the rate of spontaneous apoptosis of human peripheral blood PMNs cultured at basal (37°C) and febrile-range (39.5°C) temperatures (FRT). We found that PMN apoptosis is accelerated at FRT, reaching 
90% completion by 8 h at 39.5°C vs 18 h at 37°C based on morphologic criteria. Caspase-8 activation peaked within 15 min of PMN exposure to FRT, and subsequent activation of caspase-3 and -9, cleavage of the BH3 (Bcl-2 homology domain 3) only protein Bid, and mitochondrial release of cytochrome c were also greater in FRT-exposed PMNs. Inhibition of caspase-3, -8, and -9 conferred comparable protection from apoptosis in FRT-exposed PMNs. These results demonstrate that exposure to FRT enhances caspase-8 activation and subsequent mitochondrial-dependent and mitochondrial-independent apoptosis pathways. The PMN survival factors G-CSF, GM-CSF, and IL-8 each prolonged PMN survival at 37°C and 39.5°C, but did not reduce the difference in survival at the two temperatures. In a mouse model of intratracheal endotoxin-induced alveolitis, coexposure to FRT (core temperature 39.5°C) doubled the proportion of bronchoalveolar PMNs undergoing apoptosis compared with euthermic mice. This process may play an important role in limiting inflammation and tissue injury during febrile illnesses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by National Institutes of Health Grants GM066855, HL69057, and HL085256 (to J.D.H.) and GM069431 (to I.S.S.), and by Veterans Affairs Merit Review grants (to J.D.H. and I.S.S.).
2 Address correspondence and reprint requests to Dr. Jeffrey D. Hasday, Room 3D122 Baltimore Veterans Affairs Medical Center, 10 North Greene Street, Baltimore, MD 21201. E-mail address: jhasday{at}umaryland.edu
3 Abbreviations used in this paper: PMN, polymorphonuclear leukocyte; AEBSF, 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; AFC, 7-amino-4-trifluoromethyl-coumarin; AMC, 7-amino-4-methyl-coumarin; FRH, febrile-range hyperthermia; FRT, febrile-range (39.5°C) temperature; rh, recombinant human.
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