title: Granulocyte-macrophage colony-stimulating factor primes interleukin-13 production by macrophages via protease-activated receptor-2.
abstract: Chronic inflammation is often linked to the presence of type 2-polarized macrophages, which are induced by the T helper type 2 cytokines interleukin-4 and interleukin-13 (IL-13). IL-13 is a key mediator of tissue fibrosis caused by T helper type 2-based inflammation. Human neutrophil elastase (HNE) plays a pivotal role in the pathogenesis of pulmonary fibrosis. This study investigated the priming effect of granulocyte-macrophage colony-stimulating factor (GM-CSF) on IL-13 expression by macrophages stimulated with HNE. Adherent macrophages were obtained from primary cultures of human mononuclear cells. Expression of IL-13 mRNA and protein by GM-CSF-dependent macrophages was investigated after stimulation with HNE, using the polymerase chain reaction and enzyme-linked immunosorbent assay. GM-CSF had a priming effect on IL-13 mRNA and protein expression by macrophages stimulated with HNE, while this effect was not observed for various other cytokines. GM-CSF-dependent macrophages showed a significant increase in the expression of protease activated receptor-2 (PAR-2) mRNA and protein. The response of IL-13 mRNA to HNE was significantly decreased by pretreatment with alpha1-antitrypsin, a PAR-2 antibody (SAM11), or a PAR-2 antagonist (ENMD-1068). These findings suggest that stimulation with HNE can induce IL-13 production by macrophages, especially GM-CSF-dependent macrophages. Accordingly, neutrophil elastase may have a key role in fibrosis associated with chronic inflammation.
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Manabu
authors: M
authors: Aoki
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Rui
authors: R
authors: Yamaguchi
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Takatoshi
authors: T
authors: Yamamoto
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Yasuji
authors: Y
authors: Ishimaru
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Tomomichi
authors: T
authors: Ono
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Arisa
authors: A
authors: Sakamoto
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Shinji
authors: S
authors: Narahara
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Hiroyuki
authors: H
authors: Sugiuchi
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan.
authors: Eiji
authors: E
authors: Hirose
authors: Graduate School of Medical Science, Kumamoto Health Science University, Kumamoto, Japan. Electronic address: yamaguti@kumamoto-hsu.ac.jp.
authors: Yasuo
authors: Y
authors: Yamaguchi
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D005786:Gene Expression Regulation; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D006801:Humans; D018793:Interleukin-13 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D019272:Leukocyte Elastase / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D061251:Primary Cell Culture; D053491:Proteinase Inhibitory Proteins, Secretory / Q000494:pharmacology; D012333:RNA, Messenger / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D044464:Receptor, PAR-2 / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction; D000515:alpha 1-Antitrypsin / Q000494:pharmacology
chemical_list: C518710:1-3-methylbutyryl-N4-6-aminohexanoyl-piperazine; D000911:Antibodies, Monoclonal; C578095:IL13 protein, human; D018793:Interleukin-13; D010879:Piperazines; D053491:Proteinase Inhibitory Proteins, Secretory; D012333:RNA, Messenger; D044464:Receptor, PAR-2; D000515:alpha 1-Antitrypsin; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D019272:Leukocyte Elastase
keywords: Fibrosis; Granulocyte–macrophage colony-stimulating factor; Interleukin-13; Macrophage; Neutrophil elastase; Protease activated receptor-2