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Infection and Immunity, December 2002, p. 6896-6903, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6896-6903.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Role of Caspase 1 in Murine Antibacterial Host Defenses and Lethal Endotoxemia

Vishwas D. Joshi,1 Dhananjaya V. Kalvakolanu,2,3 John R. Hebel,4 Jeffrey D. Hasday,5 and Alan S. Cross1*

Division of Infectious Diseases,1 Pulmonary and Critical Care Medicine,5 Department of Microbiology and Immunology,2 Department of Epidemiology,4 Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland 212013

Received 9 July 2002/ Accepted 15 August 2002

Sepsis is thought to result from an exaggerated innate immune response to microbial components such as lipopolysaccharide (LPS), but the involvement of a specific mechanism(s) has not been identified. We studied the role of caspase 1 (Cas-1) in the murine innate immune response to infection with gram-negative bacteria and to nonlethal and lethal doses of LPS. cas-1-/- and Cas-1 inhibitor (Ac-YVAD-CHO)-treated cas-1+/+ mice were two- to threefold more susceptible to lethal Escherichia coli infection than cas-1+/+ mice. Administration of Cas-1 products, interleukin-18 (IL-18) or IL-1ß, protected three of three and six of seven mice, respectively, from lethal infection with E. coli compared to none of six of untreated mice (P = 0.0082). Therefore, cas-1 is essential for antibacterial host defense. Nonlethal (75 µg) and lethal (500 µg) doses of LPS induce different patterns of gamma interferon, IL-1ß, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-1ß to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 µg, LPS induced a transient increase in IL-1ß and IL-18 levels in serum, whereas at 500 µg it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 µg of LPS, splenic cas-1 mRNA expression remained unchanged at all time points, but activity increased transiently at 3 h. In lethally treated mice, Cas-1 activity remained elevated until death; however, cas-1 mRNA levels increased at 3 h and decreased to basal levels by 8 h. Treatment with Cas-1 inhibitor protected mice from lethal endotoxemia. Thus, Cas-1 is essential for innate antibacterial host defenses and may represent a mechanism of innate immunity that upon excessive stimulation by microbial components may lead to endotoxic shock.

* Corresponding author. Mailing address: MSTF 9-65, Division of Infectious Diseases, University of Maryland School of Medicine, 10 S. Pine St., Baltimore, MD 21201. Phone: (410) 706-2482. Fax: (410) 706-8700. E-mail: across{at}umm.edu.

Editor: J. D. Clements

Infection and Immunity, December 2002, p. 6896-6903, Vol. 70, No. 12
0019-9567/02/$04.00+0     DOI: 10.1128/IAI.70.12.6896-6903.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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