Heparanase prevents the development of type 1 diabetes in non-obese diabetic mice by regulating T-cell activation and cytokines production.
BACKGROUND
Heparanase is an endo-beta-D-glucuronidase that cleaves heparan sulfate saccharide chains. The enzyme promotes cell adhesion, migration and invasion, and was shown to play a significant role in cancer metastasis and angiogenesis.


METHODS
The present study focuses on the involvement of heparanase in autoimmunity, applying the murine non-obese diabetic (NOD) model, a T-cell-dependent disease often used to investigate the pathophysiology of type 1 diabetes.


RESULTS
It was found that intra-peritoneal administration of heparanase ameliorated the clinical signs of the disease. In vitro studies revealed that heparanase has an inhibitory effect on the activation of T-cells through modulation of their repertoire of cytokines indicated by a marked increase in the levels of IL-4 and IL-10, and a parallel decrease in IL-12, tumour necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma).


CONCLUSIONS
We suggest that heparanase induces a shift from a Th1- to Th2-phenotype, resulting in inhibition of diabetes in NOD mice and possibly other autoimmune disorders.
Department of Bone Marrow Transplantation, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. menachembi@tasmc.health.gov.il
Menachem
M
Bitan
Lola
L
Weiss
Michael
M
Zeira
Shoshana
S
Reich
Orit
O
Pappo
Israel
I
Vlodavsky
Shimon
S
Slavin
D000818:Animals; D016207:Cytokines / Q000096:biosynthesis*; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D005260:Female; D005966:Glucuronidase / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D018664:Interleukin-12 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D016688:Mice, Inbred NOD; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000502:physiology; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase
D016207:Cytokines; D005966:Glucuronidase; D007371:Interferon-gamma; D016753:Interleukin-10; D018664:Interleukin-12; D015847:Interleukin-4; D014409:Tumor Necrosis Factor-alpha; D000099175:Heparanase