Synergistic activation of NF-kappaB by nontypeable Haemophilus influenzae and tumor necrosis factor alpha.
Nontypeable Haemophilus influenzae (NTHi) is an important human pathogen causing otitis media in children and exacerbation of chronic obstructive pulmonary disease in adults. Like most other bacterial infections, NTHi infections are also characterized by inflammation, which is mainly mediated by cytokines and chemokines such as tumor necrosis factor alpha (TNF-alpha). Among a variety of transcription regulators, NF-kappaB has been shown to play a critical role in regulating the expression of large numbers of genes encoding inflammatory mediators. In review of the current studies on NF-kappaB regulation, most of them have focused on investigating how NF-kappaB is activated by a single inducer at a time. However, in bacteria-induced inflammation in vivo, multiple inducers including both exogenous and endogenous mediators are present simultaneously. A key issue that has yet to be addressed is whether the exogenous inducers such as NTHi and the endogenous factors such as TNF-alpha activate NF-kappaB in a synergistic manner. We show that NTHi and TNF-alpha, when present together, synergistically induce NF-kappaB activation via two distinct signaling pathways: NF-kappaB translocation-dependent and -independent pathways. The NF-kappaB translocation-dependent pathway involves NF-kappaB-inducing kinase-IkappaB kinase beta/gamma-dependent phosphorylation and degradation of IkappaBalpha, whereas the NF-kappaB translocation-independent pathway involves mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase kinase 1-dependent activation of MAPK kinase 3/6-p38 MAPK pathway. In addition, the same signaling pathways are also involved in synergistic induction of TNF-alpha, IL-1beta, and IL-8. These studies should deepen our understanding of the molecular mechanisms underlying the combinatorial regulation of inflammation and lead to development of therapeutic strategies for NTHi-induced infections.
Gonda Department of Cell and Molecular Biology, House Ear Institute, University of Southern California, Los Angeles, CA 90057, USA.
Takahiro
T
Watanabe
Hirofumi
H
Jono
Jiahuai
J
Han
David J
DJ
Lim
Jian-Dong
JD
Li
D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002478:Cells, Cultured; D006193:Haemophilus influenzae / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism; D007375:Interleukin-1 / Q000235:genetics; D016209:Interleukin-8 / Q000235:genetics; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008954:Models, Biological; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase
D017871:Calcium-Calmodulin-Dependent Protein Kinases; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins; D007375:Interleukin-1; D016209:Interleukin-8; D048371:MAP Kinase Kinase 3; D048669:MAP Kinase Kinase 6; D048728:MAP Kinase Kinase Kinase 1; D020930:MAP Kinase Kinase Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D048051:p38 Mitogen-Activated Protein Kinases; D000097782:NF-kappaB-Inducing Kinase; C000606204:NFKBIA protein, human; C496559:CHUK protein, human; C496560:IKBKB protein, human; C496565:IKBKE protein, human; C482576:MAP3K1 protein, human; C482530:MAP2K3 protein, human; C482566:MAP2K6 protein, human