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Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB

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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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Abbreviations

AC:

Apoptotic cell

CM:

Apoptotic cell-conditioned medium

ARG II:

Arginase II

MΦ:

Macrophage

mpARG II:

Murine ARG II promoter

cAMP:

Cyclic adenosine monophosphate

CREB:

cAMP responsive element binding protein

CDase:

Ceramidase

CERK:

Ceramide kinase

SMase:

Sphingomyelinase

NO:

Nitric oxide

NOE:

n-oleoyl-ethanolamine

SK2:

Sphingosine kinase 2

S1P:

Sphingosine-1-phosphate

S1P2 :

S1P receptor 2

PGE2 :

Prostaglandin E2

ERK5:

Extracellular signal-regulated kinase 5

MEK5:

Mitogen-activated protein kinase kinase 5

C1P:

Ceramide-1-phosphate

Ab:

Antibody

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Acknowledgments

This work was supported by grants from Deutsche Forschungsgemeinschaft (Br 999, FOG 784, and Excellence Cluster Cardiopulmonary System), Sander Foundation and LOEWE/LiFF. We thank Prof. Eisuke Nishida (Kyoto University, Japan) for kindly providing pcDNA3-HA1-ERK5N, pcDNA3-FLAG1-MEK5 WT and pcDNA3-FLAG1-MEK5D expression plasmids.

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Authors and Affiliations

  1. Faculty of Medicine, Institute of Biochemistry I, Goethe University Frankfurt, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany

    Vera Barra, Anne-Marie Kuhn, Andreas von Knethen, Andreas Weigert & Bernhard Brüne

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  1. Vera Barra
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  2. Anne-Marie Kuhn
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  3. Andreas von Knethen
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Correspondence to Bernhard Brüne.

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Supplemental Figure 1

. Pharmacological inhibition of SMase, CDase and CERK with GW4869, NOE and NVP231 did not interfere with staurosporine-mediated apoptosis of MCF-7 cells. MCF-7 cells were pre-incubated with 10 µM GW4869, 50 µM NOE or 0.2 µM NVP231 for 45 minutes before inducing apoptosis for 2.5 hours with staurosporine (sts) in FCS-free medium. Cell death was quantified by AnnexinV staining using FACS analysis (according to Lauber et al., Cell, Vol. 113, 717-730, 2003). Asterisk marks statistically significant differences. * p ≤ 0.05, n.s. (not significant), n ≥ 3 (JPEG 259 kb)

Supplemental Figure 2

. CM-M-dependent ARG II mRNA expression in RAW264.7 MΦs is mediated by S1P2. MΦs were incubated for 16 hours with CM-M with or without the S1P2 antagonist JTE013 (0.1 µM). The antagonist was pre-incubated for 45 minutes. ARG II mRNA expression was determined by quantitative real-time PCR. n = 4 (JPEG 210 kb)

Supplemental Figure 3

. ERK1/2 signaling does not mediated ARG II up-regulation by CM-M. RAW264.7 cells were incubated for 16 hours with CM-M with or without the specific ERK1/2 inhibitor PD98059 at the indicated concentrations. PD98059 was pre-incubated for 45 minutes. ARG II expression and ERK1/2 phosphorylation were determined by Western analysis. n ≥ 3 (JPEG 579 kb)

Supplemental Figure 4

. CM-M induces ERK5 phosphorylation in RAW264.7 MΦs. Cells were incubated with CM-M for indicated time periods. ERK5 phosphorylation was determined by Western analysis. n = 3 (JPEG 597 kb)

Supplemental Figure 5

. Sub-optimal concentrations of CM-J cannot be rescued by S1P to restore ARG II up-regulation. RAW264.7 cells were incubated for 16 hours with CM-J at a ratio of 5 ACs to 1 MΦ (5ACs:1MΦ) or 3 ACs to 1 MΦ (3ACs:1MΦ). CM-J (3ACs:1MΦ) was combined with the indicated concentrations of S1P. ARG II expression was determined by Western analysis. The graph shows quantification of ARG II expression. n ≥ 3 (JPEG 354 kb)

Supplemental Figure 6

. Physiological relevance of S1P2 signaling for ARG II expression in primary MΦs. Primary murine peritoneal MΦs from C57BL/6 mice were incubated for 16 hours with CM-M with or without the specific S1P2 antagonist JTE013 (10 µM). JTE013 was pre-incubated for 45 minutes. ARG II expression was determined by Western analysis. n = 3 (JPEG 404 kb)

Supplemental Figure 7

. Activation of adenylate cyclase with 100 µM forskolin induces ARG II expression in RAW264.7 MΦs. Cells were incubated for 16 hours with 100 µM forskolin. ARG II expression was determined by Western analysis. n = 3 (JPEG 366 kb)

Supplemental Figure 8

. RAW264.7 MΦs were stimulated for 16 hours with CM-M with or without the S1P2 antagonist JTE013 or the MEK inhibitor U0126 at the indicated concentration. Antagonists or inhibitors were pre-incubated for 45 minutes, followed by incubation with or without 100 U/ml IFNγ for 24 hours. The supernatants were harvested and nitrite levels determined by the Griess assay. iNOS expression was determined by Western analysis. n = 4 (JPEG 317 kb)

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Barra, V., Kuhn, AM., von Knethen, A. et al. Apoptotic cell-derived factors induce arginase II expression in murine macrophages by activating ERK5/CREB. Cell. Mol. Life Sci. 68, 1815–1827 (2011). https://doi.org/10.1007/s00018-010-0537-x

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