Role of caspase 1 in murine antibacterial host defenses and lethal endotoxemia.

Abstract

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-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 micro g) and lethal (500 micro g) 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-1beta to their active forms, was investigated in these disparate conditions by using enzymatic assay and reverse transcription-PCR. At 75 micro g, LPS induced a transient increase in IL-1beta and IL-18 levels in serum, whereas at 500 micro g it induced a 1.5-fold-higher IL-18 level in serum, which increased till death. At 75 micro g 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.

• Authors: Vishwas D Joshi, Dhananjaya V Kalvakolanu, John R Hebel, Jeffrey D Hasday, Alan S Cross
• Journal: Infection and immunity (Infect Immun) Vol. 70 Issue 12 Pg. 6896-903 (Dec 2002) ISSN: 0019-9567 [Print] United States
• PMID: 12438367 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Caspase Inhibitors
• Cytokines
• Lipopolysaccharides
• Caspase 1

Topics

• Animals
• Caspase 1 (genetics, metabolism)
• Caspase Inhibitors
• Cytokines (biosynthesis)
• Disease Susceptibility
• Endotoxemia (immunology, microbiology, mortality)
• Escherichia coli (pathogenicity)
• Escherichia coli Infections (immunology, microbiology, mortality)
• Female
• Immunity, Innate
• Lipopolysaccharides (pharmacology)
• Mice
• Mice, Inbred C3H
• Sepsis (immunology, mortality)
• Up-Regulation