Tumor Necrosis Factor-α Triggers Mucus Production in Airway Epithelium through an IκB Kinase β-dependent Mechanism

Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IκB kinase β (IKKβ) in mucus synthesis in vitro and in vivo. Tumor necrosis factor-α (TNF-α) or transforming growth factor-α stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF-α stimulation induced IKKβ-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-α, but not transforming growth factor-α, induced mucus production dependent on IKKβ-mediated NF-κB activation. In vivo, TNF-α induced NF-κB as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-κB-LacZ transgenic mice. TNF-α-induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKKβ dominant negative adenovirus. Taken together, our results demonstrated the important role of IKKβ in TNF-α-mediated mucus production in airway epithelium in vitro and in vivo. Excessive mucus production by airway epithelium is a major characteristic of a number of respiratory diseases, including asthma, chronic bronchitis, and cystic fibrosis. However, the signal transduction pathways leading to mucus production are poorly understood. Here we examined the potential role of IκB kinase β (IKKβ) in mucus synthesis in vitro and in vivo. Tumor necrosis factor-α (TNF-α) or transforming growth factor-α stimulation of human epithelial cells resulted in mucus secretion as measured by MUC5AC mRNA and protein. TNF-α stimulation induced IKKβ-dependent p65 nuclear translocation, mucus synthesis, and production of cytokines from epithelial cells. TNF-α, but not transforming growth factor-α, induced mucus production dependent on IKKβ-mediated NF-κB activation. In vivo, TNF-α induced NF-κB as determined by whole mouse body bioluminescence. This activation was localized to the epithelium as revealed by LacZ staining in NF-κB-LacZ transgenic mice. TNF-α-induced mucus production in vivo could also be inhibited by administration into the epithelium of an IKKβ dominant negative adenovirus. Taken together, our results demonstrated the important role of IKKβ in TNF-α-mediated mucus production in airway epithelium in vitro and in vivo. The airway epithelium is the first layer of cellular interaction with airborne antigens and plays a key role in initiating allergic responses. Research over the last decade has established a critical role for the epithelium not only by providing a physical boundary but also in transducing and integrating signals that help mount optimal responses to a wide variety of insults (1Jackson A.D. Trends Pharmacol. Sci. 2001; 22: 39-45Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, 2Adler K.B. Li Y. Am. J. Respir. Cell Mol. Biol. 2001; 25: 397-400Crossref PubMed Scopus (53) Google Scholar, 3Basbaum C. Lemjabbar H. Longphre M. Li D. Gensch E. McNamara N. Am. J. Respir. Crit. Care Med. 1999; 160: S44-S48Crossref PubMed Scopus (119) Google Scholar). Airway mucus is a highly hydrated glycoprotein exhibiting a gel state and, in combination with the ciliated cells in the airways, constitutes a mucociliary clearance system critical for protection of the respiratory tract (4Thornton D.J. Davies J.R. Carlstedt I. Sheehan J.K. Rogers D.F. Lethem M.I. Airway Mucus: Basic Mechanisms and Clinical Perspectives. Birkhäuser Verlag, Basel1997: 19-39Google Scholar). The apoprotein component of mucus is the product of a family of mucin genes (generally referred to as MUC genes), of which MUC1, -2, -3, -4, -5AC, -5B, and -7 have been shown to be expressed in airway epithelium (5Rose M.C. Gendler S.J. Rogers D.F. Lethem M.I. Airway Mucus: Basic Mechanisms and Clinical Perspectives. Birkhäuser Verlag, Basel1997: 41-66Google Scholar). Both MUC5AC and MUC2 expression have been shown to be highly regulated (6Alimam M.Z. Piazza F.M. Selby D.M. Letwin N. Huang L. Rose M.C. Am. J. Respir. Cell Mol. Biol. 2000; 22: 253-260Crossref PubMed Scopus (214) Google Scholar). Excessive mucus production is a common feature of a wide variety of respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), 2The abbreviations used are:COPDchronic obstructive pulmonary diseaseTGF-αtransforming growth factor-αTNF-αtumor necrosis factor-αIKKIκB kinaseGFPgreen fluorescent proteinWTwild typeDNdominant negativePBSphosphate-buffered salineX-gal5-bromo-4-chloro-3-indolyl-β-d-galactopyranosidepfuplaque-forming unitsLPSlipopolysaccharideMAPKmitogen-activated protein kinaseEGFRepidermal growth factor receptorILinterleukin 2The abbreviations used are:COPDchronic obstructive pulmonary diseaseTGF-αtransforming growth factor-αTNF-αtumor necrosis factor-αIKKIκB kinaseGFPgreen fluorescent proteinWTwild typeDNdominant negativePBSphosphate-buffered salineX-gal5-bromo-4-chloro-3-indolyl-β-d-galactopyranosidepfuplaque-forming unitsLPSlipopolysaccharideMAPKmitogen-activated protein kinaseEGFRepidermal growth factor receptorILinterleukin and cystic fibrosis, and constitutes a significant unmet clinical need given the lack of appropriate and effective therapies for decreasing mucus production. chronic obstructive pulmonary disease transforming growth factor-α tumor necrosis factor-α IκB kinase green fluorescent protein wild type dominant negative phosphate-buffered saline 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside plaque-forming units lipopolysaccharide mitogen-activated protein kinase epidermal growth factor receptor interleukin chronic obstructive pulmonary disease transforming growth factor-α tumor necrosis factor-α IκB kinase green fluorescent protein wild type dominant negative phosphate-buffered saline 5-bromo-4-chloro-3-indolyl-β-d-galactopyranoside plaque-forming units lipopolysaccharide mitogen-activated protein kinase epidermal growth factor receptor interleukin Despite the clinical importance of excessive mucus production, the signal transduction pathways leading to its synthesis and release from the epithelium are poorly understood. Tumor necrosis factor-α (TNF-α) is produced by diverse cell types, including macrophages, lymphocytes, fibroblasts, and keratinocytes (7Baud V. Karin M. Trends Cell Biol. 2001; 11: 372-377Abstract Full Text Full Text PDF PubMed Scopus (1367) Google Scholar, 8Locksley R.M. Killeen N. Lenardo M.J. Cell. 2001; 104: 487-501Abstract Full Text Full Text PDF PubMed Scopus (2988) Google Scholar). TNF-α is rapidly produced in response to inflammation, infection, and tissue injury and triggers a broad array of systemic and cellular responses. Through binding to its major receptor, TNFR1, TNF-α activates several intracellular signal transduction cascades, among which the nuclear factor-κB (NF-κB) pathway is of pivotal importance. In its canonical form, NF-κBisa heterodimer composed of the p50 and p65 proteins and is held in an inactive form in the cytoplasm of cells by the inhibitor of the NF-κB protein, IκBα. Upon TNFR1 engagement, a number of docking proteins are recruited to its intracellular domain, leading to the activation of the IκB kinase (IKK) complex (composed of IKKα, IKKβ, and NEMO). Subsequently, IKKβ phosphorylates IκBα at two critical serine residues, which leads to its proteasome-mediated degradation and release of the NF-κB complex. NF-κB then translocates to the nuclear compartment and acts as a transcription factor regulating the expression of numerous genes (9Chen G. Goeddel D.V. Science. 2002; 296: 1634-1635Crossref PubMed Scopus (1473) Google Scholar, 10Li Q. Verma I.M. Nat. Rev. Immunol. 2002; 2: 725-734Crossref PubMed Scopus (3275) Google Scholar). There is limited information linking NF-κB and mucus production. Proximal regulatory regions from MUC2 and MUC5AC genes have been cloned and characterized in detail (11Daizong L. Gallup M. Fan N. Szymkowsku D.E. Basbaum C.B. J. Biol. Chem. 1998; 273: 6812-6820Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 12Escande F. Aubert J.P. Porchet N. Buisine M.P. Biochem. J. 2001; 358: 763-772Crossref PubMed Scopus (52) Google Scholar). Sequence analyses of these regions have indicated the presence of NF-κB binding sequences, and electromobility shift assays and supershift experiments with specific antibodies have demonstrated binding of p50/p65 complexes to these sequences upon stimulation of cell cultures with Pseudomonas aeruginosa-derived LPS. NF-κB has been shown to play an important role in mucus production in mouse models of allergic lung inflammation (13Desmet C. Gosset P. Pajak B. Cataldo D. Bentires-Alj M. Lekeux P. Bureau F. J. Immunol. 2004; 173: 5766-5775Crossref PubMed Scopus (137) Google Scholar, 14Poynter M.E. Cloots R. vanWoerkom T. Butnor K.J. Vacek P. Taatjes D.J. Irvin C.G. Janssen-Heininger Y.M.W. J. Immunol. 2004; 173: 7003-7009Crossref PubMed Scopus (135) Google Scholar). Cell lines transfected with MUC2 reporter constructs have also suggested a role for NF-κB in LPS-induced mucus production in a pathway involving Ras-MAPK-pp90rsk (15Li J.D. Feng W. Gallup M. Kim J.H. Gum J. Kim Y. Basbaum C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5718-5723Crossref PubMed Scopus (289) Google Scholar). Along similar lines, p38 MAPK has been shown to play a role in MUC5AC up-regulation upon stimulation of normal human nasal epithelial cells and human epithelial cell lines with IL-1, TNF-α, and cytoplasmic proteins of nontypeable Haemophilus influenzae (16Wang B. Lim D.J. Han J. Kim Y.S. Basbaum C.B. Li J.D. J. Biol. Chem. 2002; 277: 949-957Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, 17Song K.S. Lee W.-J. Chung K.W. Koo J.S. Yang E.J. Choi J.Y. Yoon J.-H. J. Biol. Chem. 2003; 26: 23243-23250Abstract Full Text Full Text PDF Scopus (241) Google Scholar, 18Chen R. Lim J.H. Jono H. Gu X.-X. Kim Y.S. Basbaum C.B. Murphy T.F. Li J.-D. Biochem. Biophys. Res. Commun. 2004; 324: 1087-1094Crossref PubMed Scopus (117) Google Scholar). TGF-α-mediated EGFR tyrosine phosphorylation has also been found to play an important role in mucin elaboration in human airway epithelial cells (19Takeyama K. Dabbagh K. Lee H.M. Agustí C. Lausier J.A. Ueki I.F. Grattan K.M. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3081-3086Crossref PubMed Scopus (510) Google Scholar, 20Shao M.X.G. Ueki I.F. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 11618-11623Crossref PubMed Scopus (185) Google Scholar, 21Shao M.X.G. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 2005; 102: 767-772Crossref PubMed Scopus (227) Google Scholar). Moreover, studies where TNF-α and TGF-α were used in combination to stimulate NCI-H292 human lung epithelial cells showed an increased level of mucin protein synthesis compared with either cytokine alone, and a putative cross-talk between both signaling pathways has been hypothesized (19Takeyama K. Dabbagh K. Lee H.M. Agustí C. Lausier J.A. Ueki I.F. Grattan K.M. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3081-3086Crossref PubMed Scopus (510) Google Scholar). In the present work we have investigated the role of IKKβ in transducing the pro-inflammatory signal delivered by TNF-α and TGF-α to trigger mucus production by airway epithelial cells. Following a combination of cell culture and in vivo experiments, we show the following: first, TNF-α induces mucin and cytokine production and activates NF-κB in a human lung epithelial cell line; second, IKKβ is required for TNF-α-induced mucin and cytokine production but not for TGF-α-dependent mucus production by this human lung epithelial cell line; and third, TNF-α activates NF-κB in mouse airway epithelium in vivo and leads to goblet cell metaplasia and mucus production in an IKKβ-dependent manner. Cell Culture—NCI-H292 cells (a human pulmonary mucoepidermoid carcinoma cell line) were obtained from the American Type Culture Collection (ATCC, Manassas, VA). Cells were cultured in RPMI 1640 and at in a cells were with human TNF-α for to were as S. J. K. B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: PubMed Scopus Google expression was by the NCI-H292 cells were into to was with cells. the cultures were with and in for and the IKKβ and IKKβ for at of infection, were with the culture and with growth culture was and with with or TNF-α were in for or with a for with in for with in for at and with in for and then with or MUC5AC for at Cells were then and with a or for at Cells were and with nuclear for at with and the the were with a for with in for and in for an for from and were was and NCI-H292 cells were in of with was the to the was at for by of the for The was by and then by the and in with the was by of and the was at for The was and was used for expression was by was the and transcription was as was to to the of between two The was then with on the and on the similar and were for The for this as the reporter were that the and for these two as as the the the the the reporter from of which a fluorescent that is measured by the The for then be into the level of expression for the to the expression of for MUC5AC were as and were to for established and by the Care and at and NF-κB-LacZ transgenic C. M.P. C. S. J. 2002; 22: PubMed Google were in a with and were with and mouse TNF-α was delivered on the were and were were in and at were in optimal to and at and and were in were then in and were of p65 in of lung were as for the in vitro of were at for and then the were with and in for were with and staining and in were The was Y. of NF-κB in an reporter from with either or IKKβ in of were delivered to at of were with of TNF-α in given of at a of in of was for was as and as the system of MUC5AC in from to of the human MUC5AC was from and cloned into a from in which the been the MUC5AC reporter the transcription was from this as a and cloned into The transcription was then into an was by and to for growth and of the reporter in of were delivered to at of were for with of or of TNF-α or in given the last at a of in of was for was as and as the system TNF-α and by NCI-H292 to mucus cytokine production be by TNF-α or TGF-α in human lung epithelial NCI-H292 cells were cultured in the presence of TNF-α or TGF-α or in combination for or and and protein for MUC5AC and several cytokines were measured showed that both TNF-α and TGF-α induced MUC5AC by with at not TGF-α and TNF-α stimulation an on this MUC5AC protein increased with TNF-α and TGF-α and this response was TGF-α was used in combination with TNF-α, as revealed by TNF-α, or in combination with also induced and production TGF-α was TNF-α in cytokine TGF-α to and increased TNF-α NF-κB and MUC5AC in NCI-H292 TNF-α is a of the NF-κB we used an to its expression and intracellular in human lung epithelial cells. experiments demonstrated expression of p65 in NCI-H292 cells with the protein the cytoplasm and from the However, upon TNF-α this and p65 was found or the from and was not and was these experiments we that NCI-H292 cells have a NF-κB signaling and this pathway be by Moreover, expression of MUC5AC was with NF-κB activation. shown in at of TNF-α stimulation NF-κB the MUC5AC protein to be in the cytoplasm green NF-κB for but in NCI-H292 to NF-κB is required for mucin production in the lung we experiments of IKKβ to the dominant negative or wild type of IKKβ or a were cultures with cells were used in analyses determined by not The experiments were in and are shown in IKKβ MUC5AC expression in cells and However, IKKβ on mucin elaboration and of IKKβ to cells resulted in a of cells to similar to in cells and the of the shown in a role for NF-κB in TNF-α-induced but not in mucus production. TNF-α, TGF-α to NF-κB in NCI-H292 as determined by p65 nuclear experiments stimulation to NF-κB in NCI-H292 cells. Cells were with TNF-α or TGF-α for or or and then and for TNF-α nuclear of p65 However, TGF-α and at of the p65 in the and not to the nuclear to the are NF-κB in NCI-H292 from experiments were and protein for and measured with NF-κB activation resulted in a in and of NF-κB activation by of IKKβ was by an in cytokine production. TNF-α NF-κB in Airway in to TNF-α was for NF-κB activation in lung we used in vivo. TNF-α to the of that been with an reporter resulted in a in as compared with and with an IKKβ by to the TNF-α-mediated NF-κB activation. In to the cell TNF-α-mediated NF-κB we NF-κB-LacZ transgenic C. M.P. C. S. J. 2002; 22: PubMed Google and NF-κB activation by staining of lung of showed staining of the In lung from numerous with epithelial cells these results that administration of TNF-α to mouse induces IKKβ-mediated NF-κB activation in epithelial cells. p65 in Airway and to the of the NF-κB pathway in a and its of activation in lung epithelium in vivo, we delivered TNF-α into the of and p65 nuclear by at cells from p65 protein in the p65 nuclear was However, of TNF-α of p65 were in the nuclear with p65 was localized in the cytoplasm and not in the TNF-α Cell and in our of IKKβ-dependent mucus production in a cell culture system were of in vivo in airway TNF-α to the of that been with a reporter resulted in a in as compared with administration to an in TNF-α is to MUC5AC expression in mouse lung delivered TNF-α to for and lung were and for experiments were with a of are in and C. shown in from were However, epithelial cells from were characterized by mucin production and goblet cell metaplasia IKKβ-dependent in Airway in of TNF-α-induced p65 nuclear translocation, NF-κB and mucus production by epithelial cells to NF-κB was required for mucus production in vivo. that we TNF-α for to with a or an IKKβ adenovirus. from saline were Airway epithelium from a response that mucus production by airway epithelial cells However, mucus was upon TNF-α in IKKβ results of a pivotal role for NF-κB in TNF-α-induced mucus production in airway epithelium in vivo. The epithelium the has to to and by an response characterized by the release of cytokines and and the production of to However, in of chronic inflammation, tissue be and excessive mucus production normal lung In mucus is a common and clinical with a wide array of respiratory as asthma, and cystic fibrosis. have to be The NF-κB pathway be a for Here we show that TNF-α and TGF-α are to mucus production by lung and we to a critical role for IKKβ in but not TGF-α-dependent mucus production. epithelial cell lines, including and have been used to mucus elaboration in cell culture (15Li J.D. Feng W. Gallup M. Kim J.H. Gum J. Kim Y. Basbaum C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5718-5723Crossref PubMed Scopus (289) Google Scholar, B. Lim D.J. Han J. Kim Y.S. Basbaum C.B. Li J.D. J. Biol. Chem. 2002; 277: 949-957Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, K. Dabbagh K. Lee H.M. Agustí C. Lausier J.A. Ueki I.F. Grattan K.M. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3081-3086Crossref PubMed Scopus (510) Google Scholar, J.P. J.P. 2000; PubMed Scopus Google Scholar, R. M. T. A. M. A. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google Scholar). studies showed a potential for a number of to mucus production. TNF-α induces MUC5AC protein expression by cells in a with a at J.P. J.P. 2000; PubMed Scopus Google Scholar). In studies with NCI-H292 (19Takeyama K. Dabbagh K. Lee H.M. Agustí C. Lausier J.A. Ueki I.F. Grattan K.M. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3081-3086Crossref PubMed Scopus (510) Google mucin up-regulation by EGFR as Moreover, with specific tyrosine kinase suggested that tyrosine phosphorylation of EGFR were for mucin studies also suggested that TNF-α this response by the expression of EGFR (19Takeyama K. Dabbagh K. Lee H.M. Agustí C. Lausier J.A. Ueki I.F. Grattan K.M. Nadel J.A. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 3081-3086Crossref PubMed Scopus (510) Google Scholar, J.A. Respir. Res. 2001; 2: PubMed Scopus Google Scholar). However, in vivo of this pathway is not and the signal transduction pathway by tyrosine phosphorylation and leading to mucus production results have the of mucus production by NCI-H292 cells both TNF-α and TGF-α are used to stimulate the cells. In we show that TNF-α is to mucin up-regulation in NCI-H292 cells and that this is by There have been providing of cross-talk between the NF-κB and EGFR K. M. T. J. K. J. Biol. Chem. 2001; Full Text Full Text PDF PubMed Scopus Google NF-κB activation by of EGFR in cells. Moreover, W. I. W. Am. J. 2002; Scopus Google the of pathway on experiments airway epithelial cells. In the of mucus production, the pathway has been shown to with the NF-κB pathway to H. MUC2 expression H. T. H. H. Lim D.J. Gum J.R. Kim Y.S. S. Feng Li J.D. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google and EGFR has been shown to MUC2 and MUC5AC expression and M. P. M.C. Aubert J.P. I. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). our are the specific that the putative interaction to mucus production in airway epithelial cells. results a critical role for IKKβ to TNF-α-induced mucus production both in vitro and in vivo, and an to the of TNF-α-induced mucus production in lung also that mucus production is of NF-κB at in NCI-H292 cells. show of NF-κB nuclear and MUC5AC and protein upon TNF-α stimulation of NCI-H292 cells. Moreover, we were to MUC5AC protein expression in these cells by a dominant negative form of the IKKβ protein. studies with reporter constructs and kinase for an LPS-induced mucin expression and NF-κB activation in NCI-H292 and cell lines (15Li J.D. Feng W. Gallup M. Kim J.H. Gum J. Kim Y. Basbaum C. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 5718-5723Crossref PubMed Scopus (289) Google Scholar). In this acts the receptor which is to NF-κB Q. Verma I.M. Nat. Rev. Immunol. 2002; 2: 725-734Crossref PubMed Scopus (3275) Google Scholar). a role for IKKβ in MUC5AC we also show that NCI-H292 cells also cytokines and TNF-α stimulation and that this response is also by NF-κB has a in and inflammation Q. Verma I.M. Nat. Rev. Immunol. 2002; 2: 725-734Crossref PubMed Scopus (3275) Google Scholar, J. 2001; PubMed Scopus Google its role in specific has been in vivo in with have established a pivotal role for NF-κB in lung inflammation, in production, to the airways, and airway J. Yang L. L. P. A. Nat. Immunol. 2001; 2: PubMed Scopus Google Scholar, L. Y. J. Immunol. 1999; Google Scholar). Moreover, M.E. Irvin C.G. Janssen-Heininger Y.M.W. Am. J. 2002; 160: Full Text Full Text PDF PubMed Scopus Google showed expression of NF-κB in airway epithelium of and mice. In mouse models of allergic lung inflammation, NF-κB inflammation and mucus production (13Desmet C. Gosset P. Pajak B. Cataldo D. Bentires-Alj M. Lekeux P. Bureau F. J. Immunol. 2004; 173: 5766-5775Crossref PubMed Scopus (137) Google Scholar, 14Poynter M.E. Cloots R. vanWoerkom T. Butnor K.J. Vacek P. Taatjes D.J. Irvin C.G. Janssen-Heininger Y.M.W. J. Immunol. 2004; 173: 7003-7009Crossref PubMed Scopus (135) Google Scholar). cell culture to the potential mucus production in mouse that TNF-α administration mucus production by lung epithelial cells in vivo. the of cytokine we show that NF-κB in the TNF-α administration by as measured of an Moreover, NF-κB-LacZ we localized the of NF-κB activation to the lung on these we an TNF-α-induced mucus production in the airway epithelium in vivo. This was by the that in vivo, TNF-α-mediated mucus secretion was inhibited by an IKKβ dominant negative adenovirus. the presence of NF-κB in of and are rapidly 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Respir. J. 2001; Google Scholar, A. G. T. A. M. I. F. Chung I.M. Respir. J. 2002; PubMed Scopus Google Scholar). work a role for NF-κB in of the with these cellular TNF-α-induced mucus in the airways, and a for increased of TNF-α, and are in the of with D.M. Am. J. Respir. Crit. Care Med. Scopus Google and several studies of have suggested an between in the TNF-α with to S. K. H. Y. H. T. Am. J. Respir. Crit. Care Med. 2001; PubMed Scopus Google Scholar, M. M. Respir. Res. 2002; PubMed Scopus Google Scholar). have shown at in a human lung epithelium cell NF-κB TNF-α-induced and production. In is the and is established in Moreover, are the major of a key in is to that of TNF-α signaling by of NF-κB in the lung not only to a in mucus production but also to an of This is by results from to as a In these experiments the were inflammation and as compared with wild type A. J. H. C. Am. J. Respir. Crit. Care Med. 2002; PubMed Scopus Google Scholar). have shown that a cytokine with TNF-α, mucus production by airway and this is dependent on our NF-κB activation and mucus production in the airway epithelium in vivo TNF-α a role for NF-κB in as The of TNF-α and NF-κB with the of IKKβ as a for and of this and for also and for help with and

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