Role of caspase 1 in murine antibacterial host defenses and lethal endotoxemia.
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.
Joshi
Vishwas D
VD
Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore 21201, USA.
Kalvakolanu
Dhananjaya V
DV
Hebel
John R
JR
Hasday
Jeffrey D
JD
Cross
Alan S
AS
D000818:Animals; D020170:Caspase 1 / Q000235:genetics / Q000378:metabolism*; D061945:Caspase Inhibitors; D016207:Cytokines / Q000096:biosynthesis; D004198:Disease Susceptibility; D019446:Endotoxemia / Q000276:immunology* / Q000382:microbiology / Q000401:mortality*; D004926:Escherichia coli / Q000472:pathogenicity*; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000401:mortality; D005260:Female; D007113:Immunity, Innate; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008809:Mice, Inbred C3H; D018805:Sepsis / Q000276:immunology / Q000401:mortality; D015854:Up-Regulation
D061945:Caspase Inhibitors; D016207:Cytokines; D008070:Lipopolysaccharides; D020170:Caspase 1