Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB.
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 S1P(2), since S1P(2) 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 S1P(2) 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.
Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
Vera
V
Barra
Anne-Marie
AM
Kuhn
Andreas
A
von Knethen
Andreas
A
Weigert
Bernhard
B
Brüne
D000818:Animals; D017209:Apoptosis; D001119:Arginase / Q000378:metabolism*; D002460:Cell Line; D017077:Culture Media, Conditioned / Q000494:pharmacology; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D008246:Lysophospholipids / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology
D017077:Culture Media, Conditioned; D017362:Cyclic AMP Response Element-Binding Protein; D008246:Lysophospholipids; D034741:RNA, Small Interfering; D049349:Receptors, Lysosphingolipid; C060506:sphingosine 1-phosphate; D048054:Mitogen-Activated Protein Kinase 7; C481673:Arg2 protein, mouse; D001119:Arginase; D013110:Sphingosine