IL-18 levels and the outcome of innate immune response to lipopolysaccharide: importance of a positive feedback loop with caspase-1 in IL-18 expression.
LPS enhanced antibacterial host defenses (ABHD) when given at low (75 micro g) doses (16 of 19 mice survived 3x LD(50) Escherichia coli vs 3 of 19 LPS-naive mice; p = 0.0001), but induced lethal inflammation at high (500 micro g) doses (5 of 5 died). Differences in the cytokine profiles induced by these LPS doses may provide insight into the mechanism(s) of transition from beneficial to lethal LPS responses. The 75 micro g LPS induced 5.9 +/- 0.9 ng/ml serum IL-18 at 8 h, which decreased to 2.3 +/- 0.4 ng/ml by 24 h, whereas 500 micro g LPS induced 11.1 +/- 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 micro g, higher but sublethal (150 micro g) doses of LPS induced greater serum IL-18 levels and less effectively induced ABHD (3 of 8 survived). Reduction of serum IL-18 with neutralizing Ab improved the ABHD induced by 150 micro g, but reduced that produced by 75 micro g LPS, suggesting an optimal range of serum IL-18 level was essential for efficient ABHD. Increased expression of caspase-1 mRNA in response to the higher IL-18 levels induced at the 150 and 500 micro g, but not at the 75 micro g doses of LPS may represent a positive feedback regulatory loop leading to sustained serum IL-18 levels. We conclude that the regulation of serum IL-18 expression is critical to the outcome of innate immune responses to LPS.
Department of. Medicine, Division of Infectious Diseases, University of Maryland School of Medicine, Baltimore 21201, USA.
Vishwas D
VD
Joshi
Dhananjaya V
DV
Kalvakolanu
Jeffrey D
JD
Hasday
Richard J
RJ
Hebel
Alan S
AS
Cross
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000096:biosynthesis / Q000097:blood / Q000502:physiology; D000818:Animals; D020170:Caspase 1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004306:Dose-Response Relationship, Immunologic; D019446:Endotoxemia / Q000276:immunology / Q000382:microbiology / Q000401:mortality / Q000517:prevention & control; D004789:Enzyme Activation / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D005246:Feedback; D005260:Female; D007113:Immunity, Innate / Q000276:immunology; D007274:Injections, Intraperitoneal; D020382:Interleukin-18 / Q000008:administration & dosage / Q000096:biosynthesis* / Q000097:blood / Q000502:physiology; D007928:Lethal Dose 50; D008070:Lipopolysaccharides / Q000008:administration & dosage* / Q000276:immunology* / Q000633:toxicity; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D012333:RNA, Messenger / Q000096:biosynthesis
D000276:Adjuvants, Immunologic; D020382:Interleukin-18; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D020170:Caspase 1