IκBζ Regulates Human Monocyte Pro-Inflammatory Responses Induced by Streptococcus pneumoniae.
Pneumococcal lung infections represent a major cause of death worldwide. Single nucleotide polymorphisms (SNPs) in the NFKBIZ gene, encoding the transcription factor IκBζ, are associated with increased susceptibility to invasive pneumococcal disease. We hence analyzed how IκBζ might regulate inflammatory responses to pneumococcal infection. We first demonstrate that IκBζ is expressed in human blood monocytes but not in bronchial epithelial cells, in response to wild type pneumococcal strain D39. D39 transiently induced IκBζ in a dose dependent manner, with subsequent induction of downstream molecules involved in host defense. Of these molecules, IκBζ knockdown reduced the expression of IL-6 and GMCSF. Furthermore, IκBζ overexpression increased the activity of IL-6 and GMCSF promoters, supporting the knockdown findings. Pneumococci lacking either pneumolysin or capsule still induced IκBζ. While inhibition of TLR1/TLR2 blocked D39 induced IκBζ expression, TLR4 inhibition did not. Blockade of p38 MAP kinase and NFκB suppressed D39 induced IκBζ. Overall, our data demonstrates that IκBζ regulates monocyte inflammatory responses to Streptococcus pneumoniae by promoting the production of IL-6 and GMCSF.
Pulmonary, Allergy, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio, United States of America.
Kruthika
K
Sundaram
Department of Pharmacy, College of Pharmacy, Ohio State University, Columbus, Ohio, United States of America.|Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, United States of America.
Mohd Akhlakur
MA
Rahman
Pulmonary, Allergy, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio, United States of America.
Srabani
S
Mitra
Department of Pharmacy, College of Pharmacy, Ohio State University, Columbus, Ohio, United States of America.|Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, United States of America.
Daren L
DL
Knoell
Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, United States of America.|Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.
Shireen A
SA
Woodiga
Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, United States of America.|Center for Microbial Pathogenesis, Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States of America.|Department of Pediatrics, Ohio State University, Columbus, Ohio, United States of America.
Samantha J
SJ
King
Pulmonary, Allergy, Critical Care and Sleep Medicine, Davis Heart and Lung Research Institute, Department of Internal Medicine, Ohio State University Medical Center, Columbus, Ohio, United States of America.|Center for Microbial Interface Biology, Ohio State University, Columbus, Ohio, United States of America.
Mark D
http://orcid.org/0000-0002-7079-5633
MD
Wewers
D048868:Adaptor Proteins, Signal Transducing; D001567:Benzocycloheptenes / Q000494:pharmacology; D001980:Bronchi / Q000187:drug effects / Q000276:immunology / Q000382:microbiology; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D054884:Host-Pathogen Interactions; D006801:Humans; D020672:I-kappa B Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008070:Lipopolysaccharides / Q000494:pharmacology; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000382:microbiology; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*; D061251:Primary Cell Culture; D034741:RNA, Small Interfering / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000502:physiology*; D051194:Toll-Like Receptor 1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics / Q000276:immunology
D048868:Adaptor Proteins, Signal Transducing; D001567:Benzocycloheptenes; D020672:I-kappa B Proteins; C508600:IL6 protein, human; D015850:Interleukin-6; D008070:Lipopolysaccharides; D016328:NF-kappa B; C417234:NFKBIZ protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D048051:p38 Mitogen-Activated Protein Kinases