title: IL-1ra Secreted by ATP-Induced P2Y2 Negatively Regulates MUC5AC Overproduction via PLCβ3 during Airway Inflammation.
abstract: Mucus secretion is often uncontrolled in many airway inflammatory diseases of humans. Identifying the regulatory pathway(s) of mucus gene expression, mucus overproduction, and hypersecretion is important to alleviate airway inflammation in these diseases. However, the regulatory signaling pathway controlling mucus overproduction has not been fully identified yet. In this study, we report that the ATP/P2Y2 complex secretes many cytokines and chemokines to regulate airway inflammation, among which IL-1 receptor antagonist (IL-1ra) downregulates MUC5AC gene expression via the inhibition of Gαq-induced Ca(2+) signaling. IL-1ra inhibited IL-1α protein expression and secretion, and vice versa. Interestingly, ATP/P2Y2-induced IL-1ra and IL-1α secretion were both mediated by PLCβ3. A dominant-negative mutation in the PDZ-binding domain of PLCβ3 inhibited ATP/P2Y2-induced IL-1ra and IL-1α secretion. IL-1α in the presence of the ATP/P2Y2 complex activated the ERK1/2 pathway in a greater degree and for a longer duration than the ATP/P2Y2 complex itself, which was dramatically inhibited by IL-1ra. These findings suggest that secreted IL-1ra exhibits a regulatory effect on ATP/P2Y2-induced MUC5AC gene expression, through inhibition of IL-1α secretion, to maintain the mucus homeostasis in the airway. Therefore, IL-1ra could be an excellent modality for regulating inflamed airway microenvironments in respiratory diseases.
authors.affiliation: Department of Biochemistry, Kosin University College of Medicine, Busan 49267, Republic of Korea; Cancer Research Institute, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Jee-Yeong
authors.identifier: 0000-0001-9482-4526
authors.initials: JY
authors.lastname: Jeong
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Jiwook
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Bokyoum
authors.initials: B
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Joowon
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Yusom
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Judeok
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Anesthesiology and Pain Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Siejeong
authors.initials: S
authors.lastname: Ryu
authors.affiliation: Department of Oral Biology, BK21 PLUS Project, Yonsei University College of Dentistry, Seoul 03722, Republic of Korea.
authors.forename: Yu-Mi
authors.initials: YM
authors.lastname: Yang
authors.affiliation: Department of Physiology, Kosin University College of Medicine, Busan 49267, Republic of Korea; Institute of Medicine, Kosin University College of Medicine, Busan 49267, Republic of Korea.
authors.forename: Kyoung Seob
authors.identifier: 0000-0003-1343-2163
authors.initials: KS
authors.lastname: Song
mesh_terms: D000255:Adenosine Triphosphate; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D007249:Inflammation / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism*; D055271:Mucin 5AC / Q000378:metabolism*; D054799:Phospholipase C beta / Q000378:metabolism*; D058473:Receptors, Purinergic P2Y2 / Q000378:metabolism*
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; C524678:MUC5AC protein, human; D055271:Mucin 5AC; C546385:P2RY2 protein, human; D058473:Receptors, Purinergic P2Y2; D000255:Adenosine Triphosphate; C518039:PLCB3 protein, human; D054799:Phospholipase C beta; D002118:Calcium