Glycoconjugate Journal

, Volume 27, Issue 3, pp 329–348 | Cite as

Thymoquinone from nutraceutical black cumin oil activates Neu4 sialidase in live macrophage, dendritic, and normal and type I sialidosis human fibroblast cells via GPCR Gαi proteins and matrix metalloproteinase-9

  • Trisha M. Finlay
  • Preethi Jayanth
  • Schammim Ray Amith
  • Alanna Gilmour
  • Christina Guzzo
  • Katrina Gee
  • Rudi Beyaert
  • Myron R. Szewczuk
Article

Abstract

Anti-inflammatory activities of thymoquinone (TQ) have been demonstrated in in vitro and in vivo studies. However, the precise mechanism(s) of TQ in these anti-inflammatory activities is not well understood. Using a newly developed assay to detect sialidase activity in live macrophage cells (Glycoconj J doi: 10.1007/s10719-009-9239-8), here we show that TQ has no inhibitory effect on endotoxin lipopolysaccharide (LPS) induced sialidase activity in live BMC-2 macrophage cells. In contrast, the parent black seed oil (BSO) and another constituent of BSO para-cymene (p-CY) completely block LPS induced sialidase activity. All of these compounds had no effect on cell viability. On the other hand, TQ induces a vigorous sialidase activity in live BMC-2 macrophage cells in a dose dependent manner as well in live DC-2.4 dendritic cells, HEK-TLR4/MD2, HEK293, SP1 mammary adenocarcinoma cells, human WT and 1140F01 and WG0544 type I sialidosis fibroblast cells. Tamiflu (oseltamivir phosphate) inhibits TQ-induced sialidase activity in live BMC-2 cells with an IC50 of 0.0194 μM compared to an IC50 of 19.1 μM for neuraminidase inhibitor DANA (2-deoxy-2,3-dehydro-N-acetylneuraminic acid). Anti-Neu1, -2 and -3 antibodies have no inhibition of TQ-induced sialidase activity in live BMC-2 and human THP-1 macrophage cells but anti-Neu4 antibodies completely block this activity. There is a vigorous sialidase activity associated with TQ treated live primary bone marrow (BM) macrophage cells derived from WT and hypomorphic cathepsin A mice with a secondary Neu1 deficiency (NeuI KD), but not from Neu4 knockout (Neu4 KO) mice. Pertussis toxin (PTX), a specific inhibitor of Gαi proteins of G-protein coupled receptor (GPCR) and the broad range inhibitors of matrix metalloproteinase (MMP) galardin and piperazine applied to live BMC-2, THP-1 and primary BM macrophage cells completely block TQ-induced sialidase activity. These same inhibitory effects are not observed with the GM1 ganglioside specific cholera toxin subunit B (CTXB) as well as with CTX, tyrosine kinase inhibitor K252a, and the broad range GPCR inhibitor suramin. The specific inhibitor of MMP-9, anti-MMP-9 antibody and anti-Neu4 antibody, but not the specific inhibitor of MMP-3 completely block TQ-induced sialidase activity in live THP-1 cells, which express Neu4 and MMP-9 on the cell surface. Neu4 sialidase activity in cell lysates from TQ-treated live THP-1 cells desialylates natural gangliosides and mucin substrates. RT-PCR and western blot analyses reveal no correlation between mRNA and protein values for Neu3 and Neu4 in human monocytic THP-1 cells, suggesting for the first time a varied post-transcriptional mechanism for these two mammalian sialidases independent of TQ activation. Our findings establish an unprecedented activation of Neu4 sialidase on the cell surface by thymoquinone, which is derived from the nutraceutical black cumin oil. The potentiation of GPCR-signaling by TQ via membrane targeting of Gαi subunit proteins and matrix metalloproteinase-9 activation may be involved in the activation process of Neu4 sialidase on the cell surface.

Keywords

Thymoquinone Para-cymene Black seed oil Cell signaling Receptor activation TOLL-like receptor Neu3 sialidase Neu4 sialidase Cellular sialidase GPCR Matrix metalloproteinase 

Abbreviations

TQ

thymoquinone

p-Cy

para-cymene

Oseltamivir phosphate

Tamiflu

DANA

2-deoxy-2,3-dehydro-N-acetylneuraminic acid

LPS

lipopolysaccride

IC50

50% inhibition concentration

BM

bone marrow

M-CSF

monocyte colony-stimulating factor

4-MUNANA

2′-(4-methylumbelliferyl)-α-N-acetylneuraminic acid

PVDF

polyvinylidene fluoride

DMSO

dimethyl sulfoxide

HEK293

human embryonic kidney 293 cells

Neu1 KD

hypomorphic cathepsin A mice with the secondary ∼90% reduction of the Neu1 activity

Neu4 KO

Neu4 knockout

GPCR

G-protein coupled receptor

CTX

cholera toxin

CTXB

cholera toxin subunit B

MMP

matrix metalloproteinase

MMP-9i

specifc inhibitor of MMP-9

MMP-3i

specifc inhibitor of MMP-3

PMA

4-beta-phorbol 12-myristate 13-acetate

Notes

Acknowledgements

These studies are partially supported by grants to MRS from Natural Sciences and Engineering Research Council of Canada (NSERC). T.M.F. was a recipient of the Queen’s University Research Award. P.J. is a recipient of the Queen’s Graduate Award and the Robert J. Wilson Fellowship. S.R.A. was a recipient of the Queen’s University Research Award, the Robert J. Wilson Fellowship and the Ontario Graduate Scholarship. C.G. is a recipient of a Studentship Award from the Ontario HIV Treatment Network (OHTN). Research work on the TLR transfected cell lines is supported by grants to R.B. from the ‘Interuniversitaire Attractiepolen’ (IAP6/18), the ‘Fonds voor Wetenschappelijk Onderzoek-Vlaanderen’ (FWO; grant 3G010505), and the ‘Geconcerteerde Onderzoeksacties’ of the Ghent University (GOA; grant 01G06B6).

We acknowledge Prof. Alexey V. Pshezhetsky and Dr. Volkan Seyrantepe from the Departments of Pediatrics and Biochemistry, Montreal University, Service de Genetique, Ste-Justine Hospital, 3175 Cote-Ste-Catherine, H3T1C5, Montreal, QC, Canada for provided us the Neu1-deficient and Neu4 knockout mice as well as the sialidosis fibroblast cells.

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Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Trisha M. Finlay
    • 1
    • 4
  • Preethi Jayanth
    • 1
  • Schammim Ray Amith
    • 1
    • 5
  • Alanna Gilmour
    • 1
  • Christina Guzzo
    • 1
  • Katrina Gee
    • 1
  • Rudi Beyaert
    • 2
    • 3
  • Myron R. Szewczuk
    • 1
  1. 1.Department of Microbiology & ImmunologyQueen’s UniversityKingstonCanada
  2. 2.Department for Molecular Biomedical Research, VIB, Unit for Molecular Signal Transduction in InflammationZwijnaardeBelgium
  3. 3.Department of Biomedical Molecular BiologyGhent UniversityGhentBelgium
  4. 4.Hotchkiss Brain InstituteUniversity of CalgaryCalgaryCanada
  5. 5.Conway InstituteUniversity College DublinDublinIreland

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