15-脱氧-Δ12,14-前列腺素J2调节脂多糖诱导的内源性Cot丝裂原活化蛋白激酶激酶激酶1活性。

15-Deoxy-Delta12,14-prostaglandin J2 regulates endogenous Cot MAPK kinase kinase 1 activity induced by lipopolysaccharide.

作者信息

Caivano Matilde, Rodriguez Cristina, Cohen Philip, Alemany Susana

机构信息

Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Facultad Medicina Universidad Autónoma de Madrid, Arturo Duperier 4, 28029 Madrid, Spain.

出版信息

J Biol Chem. 2003 Dec 26;278(52):52124-30. doi: 10.1074/jbc.M306583200. Epub 2003 Oct 13.

DOI:10.1074/jbc.M306583200

PMID:14557273

Abstract

Cot is a MAPK kinase kinase that has been implicated in cellular activation and proliferation. Here, we show that the addition of lipopolysaccharide (LPS) to RAW264 macrophages induces a 10-fold increase of endogenous Cot activity, measured as MAPK kinase kinase 1 activity. Taxol, but not phorbol 12-myristate 13-acetate (PMA), induces a similar activation of Cot. A tyrosine kinase activity is involved in Cot activation by LPS. 15-Deoxy-Delta12,14-prostaglandin J2, but not rosiglitazone, blocks Cot activation by LPS. Furthermore, 15-deoxy-Delta12,14-prostaglandin J2 also inhibited the LPS-induced Cot in vitro. However, 15-deoxy-Delta12,14-prostaglandin J2 does not inhibit MAPK kinase 1 or ERK1/ERK2 activation/phosphorylation induced by PMA and mediated by c-Raf. Considering these data, we propose that the inhibition of LPS-induced Cot activation is one mechanism by which 15-deoxy-Delta12,14-prostaglandin J2 acts as an anti-inflammatory.

摘要

Cot是一种丝裂原活化蛋白激酶激酶激酶，与细胞活化和增殖有关。在此，我们表明，向RAW264巨噬细胞中添加脂多糖（LPS）会使内源性Cot活性增加10倍，以内源性丝裂原活化蛋白激酶激酶激酶1活性来衡量。紫杉醇可诱导Cot发生类似的活化，而佛波酯12-肉豆蔻酸酯13-乙酸酯（PMA）则不能。酪氨酸激酶活性参与LPS诱导的Cot活化。15-脱氧-Δ12,14-前列腺素J2可阻断LPS诱导的Cot活化，而罗格列酮则不能。此外，15-脱氧-Δ12,14-前列腺素J2在体外也抑制LPS诱导的Cot。然而，15-脱氧-Δ12,14-前列腺素J2并不抑制由PMA诱导并由c-Raf介导的丝裂原活化蛋白激酶激酶1或细胞外信号调节激酶1/细胞外信号调节激酶2的活化/磷酸化。基于这些数据，我们认为抑制LPS诱导的Cot活化是15-脱氧-Δ12,14-前列腺素J2发挥抗炎作用的一种机制。