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IL-18 Levels and the Outcome of Innate Immune Response to Lipopolysaccharide: Importance of a Positive Feedback Loop with Caspase-1 in IL-18 Expression¹

Vishwas D. Joshi^*, Dhananjaya V. Kalvakolanu^,¶, Jeffrey D. Hasday, Richard J. Hebel and Alan S. Cross^2,*,¶

Departments of ^* Medicine, Division of Infectious Diseases, Microbiology and Immunology, Medicine, Division of Pulmonary and Critical Care Medicine, and Epidemiology, and ^¶ Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201

LPS enhanced antibacterial host defenses (ABHD) when given at low (75 µg) 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 µg) 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 µg 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 µg LPS induced 11.1 ± 1.6 ng/ml serum IL-18 levels at 8 h, which increased until death. Compared with 75 µg, higher but sublethal (150 µg) 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 µg, but reduced that produced by 75 µg 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 µg, but not at the 75 µg 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.

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