title: Involvement of endogenous transforming growth factor-α in signal transduction pathway for interleukin-1β-induced hepatocyte proliferation.
abstract: We studied the effects of interleukin (IL)-1β on DNA synthesis and cell proliferation in primary cultures of adult rat hepatocytes in order to elucidate the mechanisms of its action. Hepatocyte parenchymal cells maintained in a serum-free, defined medium synthesized DNA and proliferated in the presence of IL-1β (3-30 ng/ml), but not IL-1α (0.1-30 ng/ml) in a time- and dose-dependent manner. Specific inhibitors of growth-related signal transducers, such as AG1478, LY294002, PD98059, and rapamycin, completely abolished IL-1β-stimulated hepatocyte DNA synthesis and proliferation. Western blot analysis showed that IL-1β significantly stimulated mitogen-activated protein (MAP) kinase activation within 10 min. Addition of a monoclonal antibody against transforming growth factor (TGF)-α, but not a monoclonal antibody against insulin-like growth factor-I, to the culture dose-dependently inhibited IL-1β-induced hepatocyte mitogenesis. Culture medium TGF-α levels increased significantly within 3 min in response to IL-1β from baseline levels. Peak TGF-α levels (33 pg/ml) were reached at 10 min after IL-1β stimulation. These results indicate that the proliferative mechanism of action of IL-1β is mediated through an increase in autocrine secretion of TGF-α from primary cultured hepatocytes. Secreted TGF-α, in turn, acts as a complete mitogen to induce hepatocyte mitogenesis through the receptor tyrosine kinase/phosphatidylinositol 3-kinase/MAP kinase/mammalian target of rapamycin pathway.
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, 1-1. Keyakidai, Sakado City 350-0290, Japan.
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Kimura
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, 1-1. Keyakidai, Sakado City 350-0290, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Moteki
authors.affiliation: Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, Josai University, 1-1. Keyakidai, Sakado City 350-0290, Japan. Electronic address: ogiharam@josai.ac.jp.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Ogihara
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005419:Flavonoids / Q000494:pharmacology; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D053590:Interleukin 1 Receptor Antagonist Protein / Q000378:metabolism / Q000494:pharmacology; D053582:Interleukin-1alpha / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D053583:Interleukin-1beta / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D016211:Transforming Growth Factor alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020032:Tyrphostins / Q000494:pharmacology
chemical_list: D002867:Chromones; D005419:Flavonoids; D053590:Interleukin 1 Receptor Antagonist Protein; D053582:Interleukin-1alpha; D053583:Interleukin-1beta; D009025:Morpholines; D011799:Quinazolines; D016211:Transforming Growth Factor alpha; D020032:Tyrphostins; C101044:RTKI cpd; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D004247:DNA; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D020123:Sirolimus
keywords: DNA synthesis; Interleukin-1β; Proliferation (cultured hepatocytes); Signal transduction; Transforming growth factor-α