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 mug) doses (16 of 19 mice survived 3x LD50 Escherichia coli vs 3 of 19 LPS-naive mice; p = 0.0001), but induced lethal inflammation at high (500 mug) 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 mug 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 mug LPS induced 11.1 +/- 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 mug, higher but sublethal (150 mug) 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 mug, but reduced that produced by 75 mug 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 mug, but not at the 75 mug 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.