An antiinflammatory role for IKKbeta through the inhibition of "classical" macrophage activation.
The nuclear factor kappaB (NF-kappaB) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-kappaB activation is controlled by IkappaB kinase (IKK)beta. Using Cre/lox-mediated gene targeting of IKKbeta, we have uncovered a tissue-specific role for IKKbeta during infection with group B streptococcus. Although deletion of IKKbeta in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKbeta in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKbeta in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKbeta inhibits the "classically" activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKbeta in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.
Fong
Carol Ho Yan
CH
Kennedy Institute of Rheumatology, Faculty of Medicine, Imperial College London, W6 8LH, UK.
Bebien
Magali
M
Didierlaurent
Arnaud
A
Nebauer
Ruth
R
Hussell
Tracy
T
Broide
David
D
Karin
Michael
M
Lawrence
Toby
T
D000818:Animals; D017353:Gene Deletion; D006681:HLA-D Antigens / Q000276:immunology; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000276:immunology* / Q000502:physiology*; D007113:Immunity, Innate; D007249:Inflammation / Q000503:physiopathology* / Q000517:prevention & control*; D008262:Macrophage Activation / Q000502:physiology*; D008264:Macrophages / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011018:Pneumonia, Pneumococcal / Q000276:immunology; D013290:Streptococcal Infections / Q000276:immunology; D013292:Streptococcus agalactiae
D006681:HLA-D Antigens; D051550:I-kappa B Kinase; C496560:IKBKB protein, human