A ceramide-1-phosphate analogue, PCERA-1, simultaneously suppresses tumour necrosis factor-alpha and induces interleukin-10 production in activated macrophages.
Tight regulation of the production of the key pro-inflammatory cytokine tumour necrosis factor-alpha (TNF-alpha) is essential for the prevention of chronic inflammatory diseases. In vivo administration of a synthetic phospholipid, named hereafter phospho-ceramide analogue-1 (PCERA-1), was previously found to suppress lipopolysaccharide (LPS)-induced TNF-alpha blood levels. We therefore investigated the in vitro anti-inflammatory effects of PCERA-1. Here, we show that extracellular PCERA-1 potently suppresses production of the pro-inflammatory cytokine TNF-alpha in RAW264.7 macrophages, and in addition, independently and reciprocally regulates the production of the anti-inflammatory cytokine interleukin-10 (IL-10). Specificity is demonstrated by the inability of the phospholipids ceramide-1-phosphate (C1P), sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) to perform these activities. Similar TNF-alpha suppression and IL-10 induction by PCERA-1 were observed in macrophages when activated by Toll-like receptor 4 (TLR4), TLR2 and TLR7 agonists. Regulation of cytokine production is demonstrated at the mRNA and protein levels. Finally, we show that, while PCERA-1 does not block activation of nuclear factor (NF)-kappaB and mitogen-activated protein kinases by LPS, it elevates the intracellular cAMP level. In conclusion, the anti-inflammatory activity of PCERA-1 seems to be mediated by a cell membrane receptor, upstream of cAMP production, and eventually TNF-alpha suppression and IL-10 induction. Thus, identification of the PCERA-1 receptor may provide new pharmacological means to block inflammation.
Goldsmith
Meir
M
Department of Molecular and Structural Biochemistry, Life Sciences Institute, Tel-Aviv University, Tel-Aviv, Israel.
Avni
Dorit
D
Levy-Rimler
Galit
G
Mashiach
Roi
R
Ernst
Orna
O
Levi
Maya
M
Webb
Bill
B
Meijler
Michael M
MM
Gray
Nathanael S
NS
Rosen
Hugh
H
Zor
Tsaffrir
T
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000276:immunology; D002478:Cells, Cultured; D002518:Ceramides / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology; D018836:Inflammation Mediators / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis* / Q000235:genetics; D008070:Lipopolysaccharides / Q000276:immunology; D008262:Macrophage Activation / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000276:immunology; D051193:Toll-Like Receptors / Q000819:agonists / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D000893:Anti-Inflammatory Agents; D002518:Ceramides; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; C541330:PCERA-1; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10
Chem Biol. 2005 Jun;12(6):703-15
15975516
Bioorg Med Chem. 2003 Sep 1;11(18):3937-43
12927854
J Biol Chem. 2004 May 14;279(20):20555-8
15023998
Biochem Pharmacol. 2006 Mar 14;71(6):850-7
16443193
J Biol Chem. 1997 Dec 5;272(49):31065-72
9388257
J Med Chem. 1999 Jul 1;42(13):2295-314
10395470
Bioorg Med Chem. 2002 Dec;10(12):3757-86
12413832
Cancer Cell. 2004 Sep;6(3):297-305
15380520
Nature. 2004 Sep 23;431(7007):461-6
15329734
Cytokine. 2005 Jun 21;30(6):311-8
15935951
Int J Immunopharmacol. 2000 Nov;22(11):1001-6
11090708
J Immunol. 2000 Apr 15;164(8):4277-85
10754326
J Card Fail. 1996 Dec;2(4 Suppl):S287-94
8951591
Infect Immun. 1996 Aug;64(8):3397-400
8757882
Curr Pharm Des. 2006;12(2):161-71
16454733
Anal Biochem. 1996 May 1;236(2):302-8
8660509
Bioorg Med Chem Lett. 2002 Mar 25;12(6):907-10
11958991
Nat Med. 2003 Oct;9(10):1245-50
14520364
Trends Cardiovasc Med. 2001 Apr-May;11(3-4):142-7
11686004
J Immunol. 1992 Jun 1;148(11):3441-5
1350291
Bioorg Med Chem. 2002 Dec;10(12):3807-15
12413834
J Immunol. 1999 Feb 15;162(4):2358-67
9973516
Lipids. 2007 Aug;42(8):699-706
17605061
Bioorg Med Chem Lett. 2002 Mar 25;12(6):903-5
11958990
Nature. 2004 Jul 8;430(6996):257-63
15241424
Semin Cutan Med Surg. 2007 Mar;26(1):6-14
17349557
Int Immunol. 1995 Apr;7(4):517-23
7547677
Genes Immun. 2004 Aug;5(5):315-29
14973548
J Immunol. 1999 Apr 1;162(7):4045-52
10201927
Nature. 2002 Dec 19-26;420(6917):846-52
12490957
Biochim Biophys Acta. 2006 Dec;1758(12):2049-56
16808893
Bioorg Med Chem. 2002 Dec;10(12):3787-805
12413833
Nat Chem Biol. 2006 Aug;2(8):434-41
16829954
Pathobiology. 2002-2003;70(3):177-83
12571423
Clin Immunol. 2007 May;123(2):129-38
17317321
Liver Int. 2006 Nov;26(9):1029-39
17032402
Nat Rev Mol Cell Biol. 2008 Feb;9(2):139-50
18216770
Cell Signal. 2001 Feb;13(2):85-94
11257452
Circ Res. 2006 Mar 17;98(5):642-50
16456101
Clin Transplant. 2006 Nov-Dec;20(6):788-95
17100731
Immunol Res. 2000;21(2-3):49-54
10852101
Arterioscler Thromb Vasc Biol. 2003 Jul 1;23(7):1133-6
12857714
J Rheumatol Suppl. 1999 May;57:16-21
10328138
Cell Immunol. 2004 Jan;227(1):12-23
15051511
FEBS Lett. 2000 Oct 13;483(1):57-61
11033356
J Lipid Res. 2007 Jan;48(1):66-76
17018884
Peptides. 2003 May;24(5):709-16
12895657
J Immunol. 1991 Dec 1;147(11):3815-22
1940369
J Clin Invest. 2006 Jul;116(7):1793-801
16823477
J Clin Invest. 2004 Dec;114(11):1531-7
15578083
Eur J Immunol. 2007 Mar;37(3):589-97
17301949
Mol Cell Biol. 1998 May;18(5):2815-24
9566900
Mol Pharmacol. 2005 Aug;68(2):330-5
15900018
Cell. 2001 Feb 23;104(4):487-501
11239407
Science. 2002 Apr 12;296(5566):346-9
11923495
Nature. 1994 Dec 22-29;372(6508):739-46
7997261
Am J Respir Cell Mol Biol. 1999 Apr;20(4):751-8
10101008
Cell Immunol. 2007 Jan;245(1):24-31
17466962
J Leukoc Biol. 2000 May;67(5):735-41
10811015
J Immunol. 1995 Oct 1;155(7):3552-5
7561052
J Biol Chem. 2004 Apr 2;279(14):13839-48
14732717
Nat Immunol. 2005 Dec;6(12):1228-35
16273098
J Biol Chem. 1999 Apr 2;274(14):9342-50
10092612
J Clin Invest. 2001 Jan;107(1):7-11
11134171
J Biol Chem. 1999 Jan 15;274(3):1767-75
9880559
Biochim Biophys Acta. 2006 Dec;1758(12):2016-26
16996023
Biochem Pharmacol. 2001 May 1;61(9):1153-60
11301049
J Leukoc Biol. 1994 Feb;55(2):234-40
7507969