Recombinant human IL-11 attenuates the inflammatory response through down-regulation of proinflammatory cytokine release and nitric oxide production.
To elucidate the molecular mechanisms regulating the anti-inflammatory activities of recombinant human (rh)IL-11, the ability of rhIL-11 to reduce serum levels of inflammatory mediators such as TNF-alpha, IL-1beta, IL-12, and IFN-gamma in LPS-treated mice and to down-regulate macrophage function in culture was investigated. In a mouse model of endotoxemia, pretreatment with rhIL-11 blocked LPS-induced elevation of TNF-alpha, IL-1beta, and IFN-gamma serum levels, but had no effect on IL-12 p40, IL-6, or IL-10 serum levels. The effects of rhIL-11 on the production of inflammatory mediators in vivo may occur in part through direct interactions with macrophages. rhIL-11 pretreatment of thioglycollate-elicited peritoneal macrophages resulted in greater than 60% inhibition of LPS-induced production of TNF-alpha, IL-1beta, IL-12 p40, and nitric oxide. The activity of rhIL-11 was not mediated through induction of IL-10, IL-6, or TGF-beta1. These results indicate that the ability of rhIL-11 to modulate the inflammatory response is not dependent on known anti-inflammatory cytokines and substantiate a role for this cytokine in the attenuation of inflammatory conditions.
Trepicchio
W L
WL
Preclinical Research, Genetics Institute, Cambridge, MA 02140, USA. wtrepicchio@genetics.com
Bozza
M
M
Pedneault
G
G
Dorner
A J
AJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism*; D015536:Down-Regulation; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D007375:Interleukin-1 / Q000096:biosynthesis / Q000494:pharmacology*; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009569:Nitric Oxide / Q000096:biosynthesis*; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000893:Anti-Inflammatory Agents; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D018664:Interleukin-12; D009569:Nitric Oxide