IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia.
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 blocked by IL-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-1beta 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-1beta 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.
Calkins
Casey M
CM
Department of Surgery, University of Colorado Health Sciences Center and Veterans Affairs Hospital, 4200 East 9th Avenue, Box C-313, Denver, CO 80262, USA.
Bensard
Denis D
DD
Shames
Brian D
BD
Pulido
Edward J
EJ
Abraham
Edward
E
Fernandez
Nathan
N
Meng
Xianzhong
X
Dinarello
Charles A
CA
McIntyre
Robert C
RC
D000818:Animals; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics; D002630:Chemotactic Factors / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D019446:Endotoxemia / Q000139:chemically induced / Q000378:metabolism*; D006133:Growth Substances / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D015846:Monokines / Q000096:biosynthesis / Q000235:genetics; D020556:Neutrophil Infiltration / Q000187:drug effects / Q000502:physiology*; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D009195:Peroxidase / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017472:Receptors, Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011994:Recombinant Proteins; D012486:Salmonella typhimurium / Q000276:immunology; D012795:Sialoglycoproteins / Q000494:pharmacology
C475829:CXCL1 protein, human; D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; D002630:Chemotactic Factors; C513297:Cxcl1 protein, rat; C513296:Cxcl2 protein, rat; D006133:Growth Substances; C507763:IL1RN protein, human; D036341:Intercellular Signaling Peptides and Proteins; D053590:Interleukin 1 Receptor Antagonist Protein; D008070:Lipopolysaccharides; D015846:Monokines; D012333:RNA, Messenger; D017472:Receptors, Interleukin-1; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D009195:Peroxidase