title: Heparanase upregulates Th2 cytokines, ameliorating experimental autoimmune encephalitis.
abstract: Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) saccharide chains. The enzyme promotes cell adhesion, migration and invasion and plays a significant role in cancer metastasis, angiogenesis and inflammation. The present study focuses on the involvement of heparanase in autoimmunity, applying the murine experimental autoimmune encephalitis (EAE) model, a T-cell dependent disease often used to investigate the pathophysiology of multiple sclerosis (MS). Intraperitoneal administration of recombinant heparanase ameliorated, in a dose dependent manner, the clinical signs of the disease. In vitro and in vivo studies revealed that heparanase inhibited mitogen induced splenocyte proliferation and mixed lymphocyte reaction (MLR) through modulation of their repertoire of cytokines indicated by a marked increase in the levels of IL-4, IL-6 and IL-10, and a parallel decrease in IL-12 and TNF-alpha. Similar results were obtained with active, latent, or point mutated inactive heparanase, indicating that the observed inhibitory effect is attributed to a non-enzymatic activity of the heparanase protein. We suggest that heparanase induces upregulation of Th2 cytokines, resulting in inhibition of the inflammatory lesion of EAE.
authors.affiliation: Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel.
authors.forename: Menachem
authors.initials: M
authors.lastname: Bitan
authors.forename: Lola
authors.initials: L
authors.lastname: Weiss
authors.forename: Israel
authors.initials: I
authors.lastname: Reibstein
authors.forename: Michael
authors.initials: M
authors.lastname: Zeira
authors.forename: Yakov
authors.initials: Y
authors.lastname: Fellig
authors.forename: Shimon
authors.initials: S
authors.lastname: Slavin
authors.forename: Eyal
authors.initials: E
authors.lastname: Zcharia
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Israel
authors.initials: I
authors.lastname: Vlodavsky
mesh_terms: D000818:Animals; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005966:Glucuronidase / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D013116:Spinal Cord / Q000473:pathology; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation; D000099175:Heparanase
chemical_list: D016207:Cytokines; D005966:Glucuronidase; D000099175:Heparanase
references.citation: Lab Invest. 2004 May;84(5):535-44
references.pmid: 15034597
references.citation: FASEB J. 2003 Jun;17(9):1015-25
references.pmid: 12773484
references.citation: Thromb Haemost. 2009 Nov;102(5):823-8
references.pmid: 19888515
references.citation: J Natl Cancer Inst. 2004 Aug 18;96(16):1219-30
references.pmid: 15316057
references.citation: Biochemistry. 2002 Aug 20;41(33):10519-28
references.pmid: 12173939
references.citation: J Biol Chem. 1999 Aug 20;274(34):24153-60
references.pmid: 10446189
references.citation: J Clin Invest. 2001 Jul;108(2):169-73
references.pmid: 11457867
references.citation: Nat Med. 2004 Aug;10(8):801-5
references.pmid: 15286781
references.citation: J Biol Chem. 2004 May 28;279(22):23536-41
references.pmid: 15044433
references.citation: J Exp Med. 1977 Jul 1;146(1):34-48
references.pmid: 17647
references.citation: Nature. 2001 May 17;411(6835):375-9
references.pmid: 11357145
references.citation: Proc Natl Acad Sci U S A. 1995 May 23;92(11):5037-41
references.pmid: 7761444
references.citation: Nat Rev Neurosci. 2002 Apr;3(4):291-301
references.pmid: 11967559
references.citation: Annu Rev Biochem. 1999;68:729-77
references.pmid: 10872465
references.citation: Histol Histopathol. 2000 Oct;15(4):1303-25
references.pmid: 11005254
references.citation: J Autoimmun. 1995 Oct;8(5):741-50
references.pmid: 8579728
references.citation: J Biol Chem. 2005 Apr 1;280(13):12103-13
references.pmid: 15647251
references.citation: Biochem Biophys Res Commun. 2005 May 27;331(1):175-80
references.pmid: 15845375
references.citation: J Cell Mol Med. 2007 May-Jun;11(3):427-52
references.pmid: 17635638
references.citation: Expert Opin Biol Ther. 2004 Dec;4(12):1887-96
references.pmid: 15571451
references.citation: Nat Med. 1999 Jul;5(7):793-802
references.pmid: 10395325
references.citation: J Immunol. 2006 Jun 1;176(11):6417-24
references.pmid: 16709798
references.citation: Matrix Biol. 2004 Oct;23(6):341-52
references.pmid: 15533755
references.citation: Blood. 2009 Jan 22;113(4):945-52
references.pmid: 18931341
references.citation: J Biol Chem. 2005 Sep 30;280(39):33141-8
references.pmid: 16046412
references.citation: Nat Med. 1999 Jul;5(7):803-9
references.pmid: 10395326
references.citation: Cancer Res. 2009 Mar 1;69(5):1758-67
references.pmid: 19244131
references.citation: Biochemistry. 2000 Dec 26;39(51):15659-67
references.pmid: 11123890
references.citation: Annu Rev Biochem. 1998;67:609-52
references.pmid: 9759499
references.citation: Cancer Res. 2008 Dec 15;68(24):10077-85
references.pmid: 19074873
references.citation: J Exp Med. 1995 May 1;181(5):1929-34
references.pmid: 7722469
references.citation: Immunol Res. 2003;28(3):223-39
references.pmid: 14713716
references.citation: Biochim Biophys Acta. 2001 Mar 21;1471(3):M99-108
references.pmid: 11250066
references.citation: Diabetes Metab Res Rev. 2008 Jul-Aug;24(5):413-21
references.pmid: 18561210
references.citation: J Clin Invest. 2001 Sep;108(5):739-47
references.pmid: 11544280
references.citation: J Biol Chem. 2008 Jun 27;283(26):18167-76
references.pmid: 18450756
references.citation: Curr Pharm Des. 2007;13(20):2057-73
references.pmid: 17627539
references.citation: J Cell Sci. 2004 May 1;117(Pt 11):2249-58
references.pmid: 15126626
references.citation: Curr Opin Neurol. 1999 Jun;12(3):309-21
references.pmid: 10499176
references.citation: Curr Opin Neurol. 1999 Jun;12(3):323-36
references.pmid: 10499177
references.citation: Int J Biochem Cell Biol. 2006;38(12):2018-39
references.pmid: 16901744
references.citation: Am J Pathol. 2000 Oct;157(4):1167-75
references.pmid: 11021821
references.citation: Nature. 1984 Jul 19-25;310(5974):241-4
references.pmid: 6205275
references.citation: J Leukoc Biol. 1995 Feb;57(2):207-13
references.pmid: 7852834
references.citation: Nature. 2001 Oct 4;413(6855):531-4
references.pmid: 11586362
references.citation: Protein Expr Purif. 2002 Dec;26(3):425-31
references.pmid: 12460766
references.citation: Crit Rev Immunol. 2004;24(2):111-28
references.pmid: 15581393
references.citation: Exp Hematol. 2002 Jan;30(1):34-41
references.pmid: 11823035
references.citation: J Immunol. 1998 Oct 15;161(8):4437-46
references.pmid: 9780223
references.citation: Trends Biochem Sci. 2009 Oct;34(10):511-9
references.pmid: 19733083
references.citation: J Clin Invest. 1989 Mar;83(3):752-6
references.pmid: 2493485
references.citation: Int J Biochem Cell Biol. 2008;40(3):530-42
references.pmid: 17981072
references.citation: Biochemistry. 2004 May 4;43(17):4971-7
references.pmid: 15109255
references.citation: Invasion Metastasis. 1992;12(2):112-27
references.pmid: 1399400
references.citation: Br J Biomed Sci. 2002;59(3):173-9
references.pmid: 12371064
references.citation: Br J Pharmacol. 2007 May;151(1):1-14
references.pmid: 17339837
references.citation: Biochem Biophys Res Commun. 2003 Sep 5;308(4):885-91
references.pmid: 12927802
references.citation: J Immunol. 2004 May 1;172(9):5185-93
references.pmid: 15100255
references.citation: Biochem J. 2003 Jul 15;373(Pt 2):423-35
references.pmid: 12713442
references.citation: Cytokine. 2002 Jul 21;19(2):85-93
references.pmid: 12182843