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

Abstract

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-1β, 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-1β, and IL-18 expression. Consequently, the role of Cas-1, which cleaves pro-IL-18 and pro-IL-1β 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-1β 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.