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Biochem Pharmacol. 2019 Feb 10. pii: S0006-2952(19)30047-4. doi: 10.1016/j.bcp.2019.02.009. [Epub ahead of print]

Impairment of chemical hypoxia-induced sphingosine kinase-1 expression and activation in rheumatoid arthritis synovial fibroblasts: A signature of exhaustion?

Author information

1
Centre de Recherche du Centre Hospitalier Universitaire de Québec - Université Laval, Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada.
2
Centre de Recherche du Centre Hospitalier Universitaire de Québec - Université Laval, Département de chirurgie orthopédique, Québec, QC G1V 4G2, Canada.
3
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Département de médecine, Faculté de Médecine, Université Laval, Québec, QC G1V 4G5, Canada.
4
Division of Rheumatology and Clinical Immunology, Royal Victoria Hospital, McGill University, Montreal, QC H4A 3J1, Canada.
5
Centre de Recherche du Centre Hospitalier Universitaire de Québec - Université Laval, Département de microbiologie, infectiologie et immunologie, Faculté de Médecine, Université Laval, Québec, QC G1V 4G2, Canada. Electronic address: sylvain.bourgoin@crchudequebec.ulaval.ca.

Abstract

Sphingosine kinase 1 (SphK1) and 2 (SphK2) have been shown contribute to synovial inflammation in animal models of arthritis. However, low levels of intracellular sphingosine-1 phosphate (S1P) were reported in fibroblast-like synoviocytes (FLS) from patients in the end stage of rheumatoid arthritis (RA) compared to normal FLS. Moreover, the S1P receptor-mediated chemokine synthesis was altered in RAFLS in response to chemical hypoxia. Since the mechanisms responsible for low levels of intracellular S1P in RAFLS are not fully identified, we evaluated the contribution of SphKs to the S1P-induced synthesis of chemokines under conditions of chemical hypoxia. Our results show that a chemical hypoxia mimetic cobalt chloride (CoCl2) increased SphK1 expression and activation in normal FLS but not in RAFLS. Using selective inhibitors of SphKs and gene silencing approaches, we provide evidence that both SphK1 and SphK2 are involved in hypoxia-induced chemokine production in normal FLS. In contrast, only SphK2 mediates hypoxia-induced chemokine production in RAFLS. Moreover, CoCl2 increased S1P2 and S1P3 receptor mRNA levels in normal FLS but not in RAFLS. The data suggest that altered expression and/or activation of SphK1 combined with reduced induction of S1P receptor expression by CoCl2 impaired the CoCl2-mediated autocrine S1P receptor signaling loop and chemokine production in RAFLS.

KEYWORDS:

Chemokines; Fibroblast-like synoviocytes; Rheumatoid arthritis; Sphingosine kinases; Sphingosine-1-phosphate

PMID:
30753812
DOI:
10.1016/j.bcp.2019.02.009

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