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IL-1 regulates in vivo C—X—C chemokine induction and neutrophil sequestration following endotoxemia

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,

Denis D. Bensard

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,, Division of Pediatric Surgery, The Children's Hospital, and Department of Medicine,

Brian D. Shames

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,

Edward J. Pulido

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,

Edward Abraham

Division of Pulmonary and Critical Care Medicine

Nathan Fernandez

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,

Xianzhong Meng

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital,

Charles A. Dinarello

Division of Infectious Diseases, University of Colorado Health Sciences Center, Denver, Colorado, USA

Robert C. McIntyre, JR

Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital, robert.mcintyre{at}uchsc.edu

The influx of neutrophils into tissues in response to inflammatory stimuli involves C—X—C chemokines. Interleukin-1 (IL-1) stimulates chemokine production in vitro , but its role in vivo on chemokine production is not as clearly understood. We hypothesized that IL-1 mediates in vivo tissue C—X—C chemokine production induced by systemic lipopolysaccharide (LPS). IL-1 activity was blockedbyIL-1 receptor antagonist (IL-1Ra). Rats were injected with Salmonella typhi LPS (0.5 mg/kg) with and without prior administration of IL-1Ra. Cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) protein and mRNA levels, tissue neutrophil accumulation, and indices of organ injury were measured. LPS administration resulted in increased plasma, lung, and liver IL-1ß that was decreased by IL-1Ra. LPS also induced an increase in plasma, lung, and liver CINC-1 and MIP-2 protein and mRNA. However, IL-1Ra had no effect on LPS-induced plasma or lung tissue CINC-1 levels. In contrast, IL-1Ra pretreatment did significantly decrease CINC-1 protein expression in the liver (45% decrease) and MIP-2 protein expression in plasma (100% decrease), lung (72% decrease) and liver (100% decrease) compared to LPS-treated controls. Steady-state mRNA levels by Northern blot analysis of both CINC-1 and MIP-2 in lung and liver were similar to the protein findings. Pretreatment with IL-1Ra also resulted in a 47% and 59% decrease in lung and liver neutrophil accumulation, respectively, following LPS. In addition, indices of both lung and liver injury were decreased in animals pretreated with IL-1Ra. In summary, LPS induces IL-1ß and MIP-2 expression in the lung and liver, both of which are IL-1 dependent. Although lung neutrophil accumulation in both lung and liver after LPS is also IL-1 mediated, lung CINC-1 levels were unaffected by IL-1Ra. These data suggest that IL-1 regulates tissue chemokine expression and neutrophil accumulation after LPS.

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