IL-11 regulates macrophage effector function through the inhibition of nuclear factor-kappaB.
Recombinant human IL-11 (rhIL-11) is an anti-inflammatory cytokine that can reduce the production of inflammatory mediators such as TNF-alpha, IL-1beta, IL-12, IL-6, and nitric oxide. Inhibition of proinflammatory cytokine production from activated macrophages was associated with a reduction in the levels of LPS-induced TNF-alpha, IL-1beta, IL-6, and IL-12 p40 mRNA. Analysis of rhIL-11 effects on transcription factors that activate proinflammatory cytokines demonstrated that the level of LPS-induced NF-kappaB binding activity in the nucleus of rhIL-11-treated peritoneal macrophages was significantly reduced. The block to NF-kappaB nuclear translocation correlated with the ability of rhIL-11 to maintain or increase protein levels of the inhibitors of NF-kappaB, IkappaB-alpha, and IkappaB-beta following LPS treatment. Furthermore, rhIL-11-treatment of LPS macrophages resulted in significant elevation of IkappaB-alpha and IkappaB-beta mRNA levels. These results suggest that the anti-inflammatory activity of rhIL-11 is mediated in part by inhibition of NF-kappaB-dependent transcriptional activation. Furthermore, these studies demonstrate for the first time the regulation of IkappaB-beta by an anti-inflammatory cytokine. Given the finding that inappropriate activation of NF-kappaB contributes to multiple inflammatory conditions, the ability of rhIL-11 to inhibit the binding activity of this pleiotropic transcription factor indicates that rhIL-11 has therapeutic potential in a wide range of diseases.
Trepicchio
W L
WL
Preclinical Molecular and Cellular Biology, Genetics Institute, Andover, MA 01810, USA. wtrepicchio@genetics.com
Wang
L
L
Bozza
M
M
Dorner
A J
AJ
D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D020672:I-kappa B Proteins; D007249:Inflammation / Q000276:immunology; D017370:Interleukin-11 / Q000494:pharmacology*; D008262:Macrophage Activation; D017737:Macrophages, Peritoneal / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D016207:Cytokines; D004268:DNA-Binding Proteins; C083487:I kappa B beta protein; D020672:I-kappa B Proteins; D017370:Interleukin-11; D016328:NF-kappa B; D012333:RNA, Messenger; D011994:Recombinant Proteins; C105308:oprelvekin