Pranlukast Inhibits NF-κB Activation and MUC2 Gene Expression in Cultured Human Epithelial Cells

Pranlukast is a selective cysteinyl leukotriene1 (cysLT1) receptor antagonist, and is now widely used in the treatment of asthma. The anti-asthmatic effect of pranlukast may be rendered not only by antileukotriene activity, but also by other pharmacological activity. This study was designed to investigate whether pranlukast had inhibitory effects on nuclear factor-ĸB (NF-ĸB) activation and mucin gene expression in cultured human epithelial cells. Luciferase assay was mainly used for analysis. Cultured epithelial cells were transfected with NF-ĸB luciferase vector, MUC2 or MUC5AC luciferase vectors. Lipopolysaccharide (LPS) significantly increased NF-ĸB activation in NCI-H292 cells, which was inhibited by the pretreatment by pranlukast in a dose-dependent manner. Either LTD4 or pranlukast alone did not increase NF-ĸB activation in NCI-H292 cells. Pranlukast also inhibited NF-ĸB activation induced by phorbol 12-myristate 13-acetate (PMA). Pranlukast also significantly inhibited LPS-induced MUC2 mRNA expression by reverse transcription-polymerase chain reaction (RT-PCR) analysis in NCI-H292 cells. Pranlukast also inhibited LPS-induced MUC2 gene expression in HM3-MUC2 cells. However, pranlukast did not inhibit MUC5AC gene transcription activity induced by lipoteichoic acid (LTA) in NCI-H292 cells. These results suggest that pranlukast may inhibit NF-ĸB activation and MUC2 gene transcription through pathways distinct from cysLT1 receptor antagonism in cultured human epithelial cells.

[1]  Jiahuai Han,et al.  Novel Cytoplasmic Proteins of Nontypeable Haemophilus influenzae Up-regulate Human MUC5AC Mucin Transcription via a Positive p38 Mitogen-activated Protein Kinase Pathway and a Negative Phosphoinositide 3-Kinase-Akt Pathway* , 2002, The Journal of Biological Chemistry.

[2]  J. Hiscott,et al.  Characterization of a functional NF-kappa B site in the human interleukin 1 beta promoter: evidence for a positive autoregulatory loop , 1993, Molecular and cellular biology.

[3]  Nakahara,et al.  Effects of ONO‐1078 (pranlukast) on cytokine production in peripheral blood mononuclear cells of patients with bronchial asthma , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[4]  E. Zandi,et al.  AP-1 function and regulation. , 1997, Current opinion in cell biology.

[5]  M. F. Shannon,et al.  Synergistic transcriptional activation of the IL-8 gene by NF-kappa B p65 (RelA) and NF-IL-6. , 1994, Journal of immunology.

[6]  S. Akira,et al.  Transcription factors NF-IL6 and NF-kappa B synergistically activate transcription of the inflammatory cytokines, interleukin 6 and interleukin 8. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[7]  P. Baeuerle,et al.  Regulation of tumor necrosis factor alpha transcription in macrophages: involvement of four kappa B-like motifs and of constitutive and inducible forms of NF-kappa B , 1990, Molecular and cellular biology.

[8]  Adcock Im.  Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. , 1997 .

[9]  Shizuo Akira,et al.  Toll-like receptors as adjuvant receptors. , 2002, Biochimica et biophysica acta.

[10]  P. Piper.  Formation and actions of leukotrienes. , 1984, Physiological reviews.

[11]  D. Schwartz,et al.  Neutrophils play a critical role in development of LPS-induced airway disease. , 2002, American journal of physiology. Lung cellular and molecular physiology.

[12]  J. Drazen,et al.  Prostanoid and leukotriene receptors: a progress report from the IUPHAR working parties on classification and nomenclature. , 1995, Advances in prostaglandin, thromboxane, and leukotriene research.

[13]  R. Homer,et al.  Essential Role of Nuclear Factor κB in the Induction of Eosinophilia in Allergic Airway Inflammation , 1998, The Journal of experimental medicine.

[14]  Bengt Samuelsson,et al.  Leukotrienes are potent constrictors of human bronchi , 1980, Nature.

[15]  Y. Nishizuka.  Protein kinase C and lipid signaling for sustained cellular responses , 1995, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[16]  上田 勉.  Leukotriene receptor antagonist pranlukast suppresses eosinophil infiltration and cytokine production in human nasal mucosa of perennial allergic rhinitis , 2003 .

[17]  A. Ishizaka,et al.  Effects of ONO-1078, a peptide leukotriene antagonist, on endotoxin-induced acute lung injury. , 1994, American journal of respiratory and critical care medicine.

[18]  I. Adcock.  Transcription factors as activators of gene transcription: AP-1 and NF-kappa B. , 1997, Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace.

[19]  K. Hirakawa,et al.  Leukotriene Receptor Antagonist Pranlukast Suppresses Eosinophil Infiltration and Cytokine Production in Human Nasal Mucosa of Perennial Allergic Rhinitis , 2003, The Annals of otology, rhinology, and laryngology.

[20]  T. Shimoda,et al.  Pranlukast, a cysteinyl leukotriene receptor 1 antagonist, attenuates allergen‐specific tumour necrosis factor alpha production and nuclear factor kappa B nuclear translocation in peripheral blood monocytes from atopic asthmatics , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[21]  W. Busse,et al.  Results of the first U.S. double-blind, placebo-controlled, multicenter clinical study in asthma with pranlukast, a novel leukotriene receptor antagonist. , 1997, The Journal of asthma : official journal of the Association for the Care of Asthma.

[22]  C. Labat,et al.  A second cysteinyl leukotriene receptor in human lung. , 1992, The Journal of pharmacology and experimental therapeutics.

[23]  H. Nagai,et al.  Cysteinyl leukotrienes do not mediate lipopolysaccharide-induced airway hyperresponsiveness in guinea pigs. , 1996, Prostaglandins.

[24]  Y. S. Kim,et al.  Phorbol 12-Myristate 13-Acetate Up-regulates the Transcription of MUC2 Intestinal Mucin via Ras, ERK, and NF-κB* , 2002, The Journal of Biological Chemistry.

[25]  Jian-Dong Li,et al.  Activation of NF-kappaB via a Src-dependent Ras-MAPK-pp90rsk pathway is required for Pseudomonas aeruginosa-induced mucin overproduction in epithelial cells. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[26]  T. Fukuda,et al.  Up-Regulation of Cysteinyl Leukotriene 1 Receptor by IL-13 Enables Human Lung Fibroblasts to Respond to Leukotriene C4 and Produce Eotaxin , 2003, The Journal of Immunology.

[27]  D. Brocks,et al.  The single and multiple dose pharmacokinetics of pranlukast in healthy volunteers , 1996, European Journal of Clinical Pharmacology.

[28]  Robert A. Lewis,et al.  Leukotrienes and other products of the 5-lipoxygenase pathway. Biochemistry and relation to pathobiology in human diseases. , 1990, The New England journal of medicine.

[29]  M. Copin,et al.  Expression of human mucin genes in respiratory, digestive, and reproductive tracts ascertained by in situ hybridization. , 1993, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[30]  S. Jaken.  Protein kinase C isozymes and substrates. , 1996, Current opinion in cell biology.

[31]  Michael Karin,et al.  The Beginning of the End: IκB Kinase (IKK) and NF-κB Activation* , 1999, The Journal of Biological Chemistry.

[32]  Wolfgang Ziegler,et al.  Multiple pathways control protein kinase C phosphorylation , 2000, The EMBO journal.

[33]  M. Kondo,et al.  Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. , 1997, American journal of respiratory and critical care medicine.

[34]  T. Libermann,et al.  Activation of interleukin-6 gene expression through the NF-kappa B transcription factor , 1990, Molecular and cellular biology.

[35]  T. Shimoda,et al.  Cysteinyl leukotrienes induce nuclear factor kappa b activation and RANTES production in a murine model of asthma. , 2003, The Journal of allergy and clinical immunology.

[36]  Jilly F. Evans,et al.  Characterization of the human cysteinyl leukotriene CysLT1 receptor , 1999, Nature.

[37]  S. Furukawa,et al.  Pranlukast inhibits NF‐κB activation in human monocytes/macrophages and T cells , 2003 .