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.