Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB |
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Authors: | Vera?Barra Anne-Marie?Kuhn Andreas?von?Knethen Andreas?Weigert Email author" target="_blank">Bernhard?BrüneEmail author |
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Institution: | (1) Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany; |
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Abstract: | Apoptotic cell (AC)-derived factors alter the physiology of macrophages (MΦs) towards a regulatory phenotype, characterized
by reduced nitric oxide (NO) production. Impaired NO formation in response to AC-conditioned medium (CM) was facilitated by
arginase II (ARG II) expression, which competes with inducible NO synthase for l-arginine. Here we explored signaling pathways allowing CM to upregulate ARG II in RAW264.7 MΦs. Sphingosine-1-phosphate (S1P)
was required and acted synergistically with a so far unidentified factor to elicit high ARG II expression. S1P activated S1P2, since S1P2 knockdown prevented ARG II upregulation. Furthermore, ERK5 knockdown attenuated CM-mediated ARG II protein induction. CREB
was implicated as shown by EMSA analysis and decoy-oligonucleotides scavenging CREB in RAW264.7 MΦs, which blocked ARG II
expression. We conclude that AC-derived S1P binds to S1P2 and acts synergistically with other factors to activate ERK5 and concomitantly CREB. This signaling cascade shapes an anti-inflammatory
MΦ phenotype by ARG II induction. |
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