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.