Pathway Report

Name	NF-kB activation by non-typable Haemophilus in?uenzae
BioCarta Link	ID: NTHI_PATHWAY Name: nthi pathway Brief Description: NFkB activation by Nontypeable Hemophilus influenzae Full Description: The role of Hemophilus influenzae in ear infections and chronic obstructive pulmonary disease includes the induction of an inflammatory response through activation of the transcription factor NF-kB. In addition to activation of inflammatory cytokine genes like IL-1 and TNF, H. influenzae activates TLR2 expression and genes involved in mucus production. Hemophilus influenzae activates NF-kB by multiple mechanisms, starting with activation of the Toll-like receptor 2 (TLR2) by the p16 protein in the H. influenzae outer membrane. TLR2 plays a key role in innate immune responses and is expressed in high levels in lymphoid cells as well as low levels in epithelial cells. The role of TLR2 was supported by blocking NF-kB activation with a dominant negative TLR2 and increasing it with transfection of a normal TLR2 gene. TLR2 in turn activates TAK1, which activates two divergent signaling pathways. One of these pathways leads to IkB kinase activation, IkB phosphorylation and degradation, releasing the NF-kB heterodimer to translocate into the nucleus and activate transcription of target genes. In the alternate pathway, TAK1 also activates NF-kB through a Map kinase pathway, activating p38 and NF-kB in a nuclear translocation independent manner. Investigation of the mechanisms of H. influenzae signaling involved in NF-kB activation may provide the information needed to develop better treatments for inflammatory conditions caused by this pathogen. Other pathways modulate the role of NF-kB in H. influenzae pathogenesis. Glucocorticoids widely used as anti-inflammatory drugs increase TLR2 activation by H. influenzae through the NIK/I-kB kinase pathway, while they repress the p38 dependent activation of NF-kB. The repression of the p38 pathway by glucocorticoids occurs through activation of the MAP kinase phosphatase-1 (MKP-1) which dephosphorylates and deactivates p38. Another aspect of the inflammatory response to H. influenzae infection is the production of excessive mucus, contributing to the overall symptoms of infection. NF-kB activation of the Muc2 gene contributes to mucus overproduction, in addition to H. influenzae activation of the TGF-beta receptor, activating SMAD transcription factors SMAD3 and SMAD4. Understanding mechanisms that modify H. influenzae signaling will contribute to further understanding the pathogenesis and treatment of ear infections and chronic obstructive pulmonary disease.
No. of Studies (Positive/Negative)	1 (1/0)

Name in Literature	Reference	Research Type	Statistical Result	Relation Description
NF-kB activation by non-typable Haemophilus in?uenzae	Kao CF, 2012	patients and normal controls		We found 17 significantly enriched pathways for depression We found 17 significantly enriched pathways for depression

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Genetic/Epigenetic Locus	Protein and Other Molecule	Cell and Molecular Pathway	Neural System	Cognition and Behavior	Symptoms and Signs	Environment	MDD

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Approved Symbol	Approved Name	Type	No. of Studies (Positive/Negative)
IL8	interleukin 8	Literature-origin	1(1/0)
TNF	tumor necrosis factor	Literature-origin; SNP mapped; Protein mapped	5(5/0)
EP300	E1A binding protein p300	Literature-origin	1(1/0)
CREBBP	CREB binding protein	Literature-origin	1(0/1)
NFKB1	nuclear factor of kappa light polypeptide gene enhancer in B-cells 1	Protein mapped	0(0/0)
NR3C1	nuclear receptor subfamily 3, group C, member 1 (glucocorticoid receptor)	Literature-origin; SNP mapped; Protein mapped	7(7/0)
IL1B	interleukin 1, beta	Literature-origin; SNP mapped; Protein mapped	3(2/1)