Tofacitinib inhibits granulocyte-macrophage colony-stimulating factor-induced NLRP3 inflammasome activation in human neutrophils

被引:43
作者
Furuya, Makiko Yashiro [1 ]
Asano, Tomoyuki [1 ]
Sumichika, Yuya [1 ]
Sato, Shuzo [1 ]
Kobayashi, Hiroko [1 ]
Watanabe, Hiroshi [1 ]
Suzuki, Eiji [2 ]
Kozuru, Hideko [3 ]
Yatsuhashi, Hiroshi [3 ]
Koga, Tomohiro [4 ]
Ohira, Hiromasa [5 ]
Sekine, Hideharu [6 ]
Kawakami, Atsushi [4 ]
Migita, Kiyoshi [1 ]
机构
[1] Fukushima Med Univ, Sch Med, Dept Rheumatol, 1 Hikarigaoka, Fukushima, Fukushima 9601295, Japan
[2] Ohta Nishinouchi Gen Hosp Fdn, Dept Rheumatol, 2-5-20 Nishinouchi, Koriyama, Fukushima 9638558, Japan
[3] NHO Nagasaki Med Ctr, Clin Res Ctr, Kubara 2-1001-1, Omura, Nagasaki 8568562, Japan
[4] Nagasaki Univ, Grad Sch Biomed Sci, Unit Translat Med, Dept Immunol & Rheumatol, Sakamoto 1-7-1, Nagasaki 8528501, Japan
[5] Fukushima Med Univ, Sch Med, Dept Gastroenterol, 1 Hikarigaoka, Fukushima, Fukushima 9601295, Japan
[6] Fukushima Med Univ, Sch Med, Dept Immunol, 1 Hikarigaoka, Fukushima, Fukushima 9601295, Japan
关键词
Granulocyte-macrophage colony-stimulating factor; Inflammasome; Interleukin-1; beta; Janus kinase; Neutrophils; NLR family pyrin domain-containing 3; Tofacitinib; TARGETING GM-CSF; RHEUMATOID-ARTHRITIS; TREATING INFLAMMATION; AUTOIMMUNE-DISEASES; CP-690,550; CYTOKINES; DRIVES;
D O I
10.1186/s13075-018-1685-x
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Background: Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine that activates myeloid cells to initiate tissue inflammation. However, the molecular actions of GM-CSF against innate immunity are still poorly characterized. Here, we investigated the in vitro effects of GM-CSF on the activation of human myeloid lineages, neutrophils, and the underlying intracellular signaling mechanism, including inflammasome activation. Methods: Human neutrophils were stimulated with GM-CSF in the presence or absence of tofacitinib. The cellular supernatants were analyzed for interleukin-1 beta (IL-1 beta) and caspase-1 by enzyme-linked immunosorbent assay (ELISA) methods. Pro-IL-1 beta mRNA expressions in human neutrophils were analyzed by real-time polymerase chain reaction. Protein phosphorylation of neutrophils was assessed by Western blot using phospho-specific antibodies. Results: Stimulation with GM-CSF alone, but not tumor necrosis factor-alpha, was shown to increase the release of IL-1 beta and cleaved caspase-1 (p20) from human neutrophils. Tofacitinib, which inhibits GM-CSF-induced Janus kinase 2 (Jak2)-mediated signal transduction, completely abrogated GM-CSF-induced IL-1 beta and caspase-1 (p20) secretion from neutrophils. GM-CSF stimulation also induced pro-IL-1 beta mRNA expression in neutrophils and induced NLR family pyrin domain-containing 3 (NLRP3) protein expression. Although tofacitinib pretreatment marginally inhibited GM-CSF-induced pro-IL-1 beta mRNA expression, tofacitinib completely abrogated NLRP3 protein expression in neutrophils. Conclusions: These results indicate that GM-CSF signaling induces NLRP3 expression and subsequent IL-1 beta production by affecting neutrophils, which may cause the activation of innate immunity. Therefore, GM-CSF is a key regulator of the NLRP3 inflammasome and IL-1 beta production by activating innate immune cells. This process can be blocked by tofacitinib, which interferes with JAK/STAT signaling pathways.
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页数:9
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