{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T03:03:19Z","timestamp":1792724599062,"version":"4.5.0"},"reference-count":39,"publisher":"National Academy of Sciences","issue":"15","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2001,7,17]]},"abstract":"<jats:p>\n                    Nontypeable\n                    <jats:italic>Hemophilus influenzae<\/jats:italic>\n                    (NTHi) is an important human pathogen in both children and adults. In children, it causes otitis media, the most common childhood infection and the leading cause of conductive hearing loss in the United States. In adults, it causes lower respiratory tract infections in the setting of chronic obstructive pulmonary disease, the fourth leading cause of death in the United States. The molecular mechanisms underlying the pathogenesis of NTHi-induced infections remain undefined, but they may involve activation of NF-\u03baB, a transcriptional activator of multiple host defense genes involved in immune and inflammatory responses. Here, we show that NTHi strongly activates NF-\u03baB in human epithelial cells via two distinct signaling pathways, NF-\u03baB translocation-dependent and -independent pathways. The NF-\u03baB translocation-dependent pathway involves activation of NF-\u03baB inducing kinase (NIK)\u2013IKK\u03b1\/\u03b2 complex leading to I\u03baB\u03b1 phosphorylation and degradation, whereas the NF-\u03baB translocation-independent pathway involves activation of MKK3\/6\u2013p38 mitogen-activated protein (MAP) kinase pathway. Bifurcation of NTHi-induced NIK\u2013IKK\u03b1\/\u03b2-I\u03baB\u03b1 and MKK3\/6\u2013p38 MAP kinase pathways may occur at transforming growth factor-\u03b2 activated kinase 1 (TAK1). Furthermore, we show that toll-like receptor 2 (TLR2) is required for NTHi-induced NF-\u03baB activation. In addition, several key inflammatory mediators including IL-1\u03b2, IL-8, and tumor necrosis factor-\u03b1 are up-regulated by NTHi. Finally, P6, a 16-kDa lipoprotein highly conserved in the outer membrane of all NTHi and\n                    <jats:italic>H. influenzae<\/jats:italic>\n                    type b strains, appears to also activate NF-\u03baB via similar signaling pathways. Taken together, our results demonstrate that NTHi activates NF-\u03baB via TLR2\u2013TAK1-dependent NIK\u2013IKK\u03b1\/\u03b2-I\u03baB\u03b1 and MKK3\/6\u2013p38 MAP kinase signaling pathways. These studies may bring new insights into molecular pathogenesis of NTHi-induced infections and open up new therapeutic targets for these diseases.\n                  <\/jats:p>","DOI":"10.1073\/pnas.151236098","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:34:10Z","timestamp":1027679650000},"page":"8774-8779","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":222,"title":["Activation of NF-\u03baB by nontypeable\n                    <i>Hemophilus influenzae<\/i>\n                    is mediated by toll-like receptor 2-TAK1-dependent NIK\u2013IKK\u03b1\/\u03b2\u2013I\u03baB\u03b1 and MKK3\/6\u2013p38 MAP kinase signaling pathways in epithelial cells"],"prefix":"10.1073","volume":"98","author":[{"given":"Tsuyoshi","family":"Shuto","sequence":"first","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haidong","family":"Xu","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beinan","family":"Wang","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahuai","family":"Han","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hirofumi","family":"Kai","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin-Xing","family":"Gu","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy F.","family":"Murphy","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Lim","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian-Dong","family":"Li","sequence":"additional","affiliation":[{"name":"Gonda Department of Cell and Molecular Biology, House Ear Institute and the Department of Otolaryngology, University of Southern California, Los Angeles, CA 90057; Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037; Department of Pharmacological Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Laboratory of Immunology, National Institute of Deafness and Other Communication Disorders, Rockville, MD 20850; and Division of Infectious Diseases, State University of New..."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2001,7,3]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1128\/MMBR.62.2.294-308.1998"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-200005001-00003"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198206103062305"},{"key":"e_1_3_3_4_2","doi-asserted-by":"crossref","first-page":"78S","DOI":"10.1164\/ajrccm\/152.5_Pt_2.S78","volume":"152","year":"1995","unstructured":"Am J Respir Crit Care Med 152, Suppl. 5, 78S\u2013121S (1995).","journal-title":"Am J Respir Crit Care Med"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1053\/srin.2000.0150041"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-200005001-00007"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI2865"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.68.7.4024-4031.2000"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(99)00050-3"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0092-8674(00)80413-4"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203219"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1574-695X.1999.tb01384.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/165-Supplement_1-S181"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.18.10.5899"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.17.11096"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1074-7613(00)80449-5"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1038\/26239"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1038\/18465"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.70.9.5777-5785.1996"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1084\/jem.184.5.1663"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/152.6.1300"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1128\/iai.59.8.2658-2663.1991"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.17.9090"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.289.5484.1560"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0171-2985(97)80025-3"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(99)00071-6"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1203174"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.272.19.12422"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.10.5718"},{"key":"e_1_3_3_30_2","first-page":"96","volume":"2","author":"Adams J L","year":"1999","unstructured":"J L Adams, D Lee Curr Opin Drug Discovery Dev 2, 96\u2013109 (1999).","journal-title":"Curr Opin Drug Discovery Dev"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/35021228"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0952-7915(99)00045-X"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200008033430506"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1038\/41131"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.274.47.33419"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.25.14459"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.94.3.967"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006454-200005001-00013"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199506083322307"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.151236098","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T23:54:59Z","timestamp":1649807699000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.151236098"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2001,7,3]]},"references-count":39,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2001,7,17]]}},"alternative-id":["10.1073\/pnas.151236098"],"URL":"https:\/\/doi.org\/10.1073\/pnas.151236098","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2001,7,3]]},"assertion":[{"value":"2000-11-16","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-05-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2001-07-03","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}