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A proinflammatary role of Mlkl dependent necroptosis in pancreatitis
Author(s) -
Ren Junming
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1119.8
Subject(s) - necroptosis , proinflammatory cytokine , inflammation , biology , spleen , pancreatitis , pancreas , knockout mouse , programmed cell death , apoptosis , cancer research , medicine , endocrinology , immunology , gene , biochemistry
Rip3 was reported to play a pivotal role in various pathophysiological conditions, such as Crohn's disease, hepatitis, atherosclerosis and systemic inflammatory response syndrome. To determine whether Mlkl also plays a role in the progression of necroptosis‐associated diseases, we generated Mlkl knockout mice by gene disruption. Homozygous Mlkl‐deficient (Mlkl−/−) mice are viable, healthy, fertile, born with normal Mendelian frequency and do not display any gross physical or behavioral abnormalities. The expression pattern of Mlkl is quite different from that of Rip3. The expression level of Mlkl protein is high in thymus, colon, intestine, liver, spleen and lung, much lower in skeletal muscle, heart and kidney, and undetectable in the brain. We analyzed wild‐type and Mlkl−/− mice in an acute pancreatitis mouse model induced by cerulein stimulation. Wild‐type mice injected with cerulein every hour for 6 consecutive hours showed much more severe acinar cell necrosis than Mlkl−/− littermates under the same treatment; phosphorylation of Mlkl was detected in wild‐type but not Mlkl−/− acinar cells, and many more inflammatory cells, such as macrophages, neutrophils and other granulocytes, were found in wild‐type compared to Mlkl−/− pancreas and blood. The mRNA expression levels of 5 inflammatory cytokines, including IL‐6 and KC, were decreased significantly in the pancreas of mice lacking Mlkl. Our findings indicate that necroptosis plays a strong proinflammatory role in pancreatitis.