Journal
INFECTION AND IMMUNITY
Volume 70, Issue 12, Pages 6896-6903Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/IAI.70.12.6896-6903.2002
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Funding
- NCI NIH HHS [R01 CA078282, CA78282, CA71401] Funding Source: Medline
- NIAID NIH HHS [AI40568] Funding Source: Medline
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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-WAD-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-1beta, 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 mug) and lethal (500 mug) doses of LPS induce different patterns of gamma interferon, IL-1beta, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-Ibeta to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 mug, LPS induced a transient increase in IL-1beta and IL-18 levels in serum, whereas at 500 mug it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 jig 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 3 111 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.
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