title: Silencing of MUC8 by siRNA increases P2Y₂-induced airway inflammation.
abstract: Mucin hypersecretion and overproduction are frequent manifestations of respiratory disease. Determining the physiological function of airway mucin is presently considered more important than identifying the relevant signaling pathways. The lack of a full-length human mucin 8 (MUC8) cDNA sequence has hindered the generation of a Muc8 knockout mouse line. Thus, the precise physiological functions of MUC8 are unclear. Herein, we investigated the function of MUC8 using a small-interfering RNA (siRNA)-mediated genetic silencing approach in human airway epithelial cells. Herein, intracellular IL-1α production was stimulated by an ATP/P2Y2 complex. While ATP/P2Y₂ increased IL-1α secretion in a time-dependent manner, treatment with P2Y₂-specific siRNA significantly decreased IL-1α secretion. Moreover, ATP increased P2Y₂-mediated upregulation of MUC8 expression; however, IL-1α significantly decreased the extent to which ATP/P2Y₂ upregulated MUC8 expression. Interestingly, treatment with MUC8-specific siRNA decreased the production of anti-inflammatory cytokines (TGF-β and IL-1 receptor antagonist) and increased the production of inflammatory cytokines (IL-1α and IL-6) in our system. In addition, siRNA-mediated knockdown of MUC8 expression dramatically increased the secretion of inflammatory chemokines and resulted in an approximately threefold decrease in cell chemotaxis. We propose that MUC8 may function as an anti-inflammatory mucin that participates in inflammatory response by attracting immune cells/cytokines to the site of inflammation. Our results provide new insight into the physiological function of MUC8 and enhance our understanding of mucin overproduction during airway inflammation.
authors.affiliation: Department of Parasitology and Genetics, Kosin University College of Medicine, Busan, Korea; Institute of Medicine, Kosin University College of Medicine, Busan, Korea;
authors.forename: Hee-Jae
authors.initials: HJ
authors.lastname: Cha
authors.affiliation: Department of Physiology, Kosin University College of Medicine, Busan, Korea;
authors.forename: Min-Su
authors.initials: MS
authors.lastname: Jung
authors.affiliation: Department of Physiology, Kosin University College of Medicine, Busan, Korea;
authors.forename: Do Whan
authors.initials: do W
authors.lastname: Ahn
authors.affiliation: Department of Physiology, Kosin University College of Medicine, Busan, Korea;
authors.forename: Jang-Kyu
authors.initials: JK
authors.lastname: Choi
authors.affiliation: Department of Parasitology and Genetics, Kosin University College of Medicine, Busan, Korea;
authors.forename: Mee Sun
authors.initials: MS
authors.lastname: Ock
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, Chung-Ang University School of Medicine, Seoul, Korea;
authors.forename: Kyung Soo
authors.initials: KS
authors.lastname: Kim
authors.affiliation: Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, Korea; and.
authors.forename: Joo-Heon
authors.initials: JH
authors.lastname: Yoon
authors.affiliation: Department of Veterinary Physiology, College of Veterinary Medicine, Seoul National University, Seoul, Korea kssong@kosin.ac.kr.
authors.forename: Eun Ju
authors.initials: EJ
authors.lastname: Song
authors.affiliation: Institute of Medicine, Kosin University College of Medicine, Busan, Korea; Department of Physiology, Kosin University College of Medicine, Busan, Korea;
authors.forename: Kyoung Seob
authors.initials: KS
authors.lastname: Song
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D020868:Gene Silencing; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009077:Mucins / Q000096:biosynthesis* / Q000235:genetics; D034741:RNA, Small Interfering; D058473:Receptors, Purinergic P2Y2 / Q000235:genetics / Q000378:metabolism*; D012140:Respiratory Tract Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: C508584:IL1A protein, human; C507763:IL1RN protein, human; C508600:IL6 protein, human; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D015850:Interleukin-6; C105059:MUC8 protein, human; D009077:Mucins; D034741:RNA, Small Interfering; D058473:Receptors, Purinergic P2Y2; D016212:Transforming Growth Factor beta; D000255:Adenosine Triphosphate
keywords: adenosine 5′-triphosphate; inflammatory cytokines; mucin 8; small-interfering ribonucleic acid