Sphingosine kinase-1 mediates TNF-α-induced MCP-1 gene expression in endothelial cells: upregulation by oscillatory flow

In this study, we report that low doses of tumor necrosis factor-a (TNFa) promote myogenesis in C2C12 myoblasts. Moreover, the cytokine increased sphingosine kinase (SphK) activity and induced SphK1 translocation to membranes. The inhibition of SphK functionality by various approaches abrogated the pro-myogenic effect of TNFa. Moreover, silencing of S1P 2 impaired the positive action of TNFa on myogenesis. These results represent the first evidence that SphK/S1P 2 axis is required for the regulation of myogenesis by TNFa. In view of the physiological role of TNFa in muscle regeneration, the present finding reinforces the notion that SphK/S1P 2 signaling is critically implicated in myogenesis.

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“…This hypothesis is also corroborated by the observed SphKdependency of p38 MAPK activation by TNFa in endothelial cells [19].…”

Section: Discussionsupporting

confidence: 54%

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P₂ signaling

et al. 2007

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“…These observations suggest that MCP-1 production in macrophages is also controlled by the SK1-S1P pathway. This finding is in agreement with previous reports showing that incubation of human mammary endothelial cells and a neuroblastoma cell line with extracellular S1P increases MCP-1 expression in a time-and concentration-dependent manner (44,45).…”

Section: Discussionsupporting

confidence: 94%

The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1–Sphingosine 1-Phosphate Pathway

et al. 2015

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cCryptococcus neoformans is a fungal pathogen that causes pulmonary infections, which may progress into life-threatening meningitis. In commonly used mouse models of C. neoformans infections, fungal cells are not contained in the lungs, resulting in dissemination to the brain. We have previously reported the generation of an engineered C. neoformans strain (C. neoformans ⌬gcs1) which can be contained in lung granulomas in the mouse model and have shown that granuloma formation is dependent upon the enzyme sphingosine kinase 1 (SK1) and its product, sphingosine 1-phosphate (S1P). In this study, we have used four mouse models, CBA/J and C57BL6/J (both immunocompetent), Tg26 (an isogenic strain of strain CBA/J lacking T and NK cells), and SK ؊/؊ (an isogenic strain of strain C57BL6/J lacking SK1), to investigate how the granulomatous response and SK1-S1P pathway are interrelated during C. neoformans infections. S1P and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the bronchoalveolar lavage fluid of all mice infected with C. neoformans ⌬gcs1 but not in mice infected with the C. neoformans wild type. SK1؊/؊ mice did not show elevated levels of S1P or MCP-1. Primary neutrophils isolated from SK1 ؊/؊ mice showed impaired antifungal activity that could be restored by the addition of extracellular S1P. In addition, high levels of tumor necrosis factor alpha were found in the mice infected with C. neoformans ⌬gcs1 in comparison to the levels found in mice infected with the C. neoformans wild type, and their levels were also dependent on the SK1-S1P pathway. Taken together, these results suggest that the SK1-S1P pathway promotes host defense against C. neoformans infections by regulating cytokine levels, promoting extracellular killing by phagocytes, and generating a granulomatous response. C ryptococcosis is a serious fungal infection in immunocompromised hosts that results in deadly meningitis once fungi disseminate to the central nervous system (CNS) (1-3). Cryptococcus neoformans is a common environmental fungus, and exposure is thought to be extremely prevalent but rarely progresses to disease in healthy individuals (4-6). Most human hosts are able to combat and contain C. neoformans in the lungs to prevent spread to the CNS. A successful immune response results in the killing of C. neoformans and the formation of a granuloma in the lungs, which is thought to prevent C. neoformans from accessing the vasculature and causing infection of the CNS. Under conditions of immune suppression, this response does not occur successfully and C. neoformans survives within macrophages, which are thought to transport C. neoformans across the blood-brain barrier and lead to life-threatening meningitis (3, 5). Although significant work has been done to elucidate the role of the host defense during early pulmonary infection, much work regarding the development of a granuloma in response to C. neoformans remains to be done (7,8).Despite the induction of proinflammatory cytokines in commonly used mouse mode...

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“…Human SPHK1-specific 21-nucleotide siRNA oligo (Dharmacon Research; GAGCUGCAAGGCCUUGCCCdTdT and GGGCAAGGCCUUGCAG CUCdTdT) targets 70 nt downstream of the start codon as described previously (23)(24)(25). These previous studies also showed that the above SPHK1 siRNA specifically inhibits SPHK1 mRNA expression.…”

Section: Transfection Of Sirnamentioning

confidence: 96%

Sphingosine Kinase 1 Is a Negative Regulator of CD4+ Th1 Cells

Yang

Castle

Hanidu

et al. 2005

The Journal of Immunology

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CD4+ Th1 cells produce IFN-γ, TNF-α, and IL-2. These Th1 cytokines play critical roles in both protective immunity and inflammatory responses. In this study we report that sphingosine kinase 1 (SPHK1), but not SPHK2, is highly expressed in DO11.10 Th1 cells. The expression of SPHK1 in Th1 cells requires TCR signaling and new protein synthesis. SPHK1 phosphorylates sphingosine to form sphingosine-1-phosphate. Sphingosine-1-phosphate plays important roles in inhibition of apoptosis, promotion of cell proliferation, cell migration, calcium mobilization, and activation of ERK1/2. When SPHK1 expression was knocked down by SPHK1 short interfering RNA, the production of IL-2, TNF-α, and IFN-γ by Th1 cells in response to TCR stimulation was enhanced. Consistently, overexpression of dominant-negative SPHK1 increased the production of IL-2, TNF-α, and IFN-γ in Th1 cells. Furthermore, overexpression of SPHK1 in Th1 and Th0 cells decreased the expression of IL-2, TNF-α, and IFN-γ. Several chemokines, including Th2 chemokines CCL17 and CCL22, were up-regulated by SPHK1 short interfering RNA and down-regulated by overexpression of SPHK1. We also showed that Th2 cells themselves express CCL17 and CCL22. Finally, we conclude that SPHK1 negatively regulates the inflammatory responses of Th1 cells by inhibiting the production of proinflammatory cytokines and chemokines.

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Sphingosine kinase-1 mediates TNF-α-induced MCP-1 gene expression in endothelial cells: upregulation by oscillatory flow

Cited by 76 publications

References 42 publications

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P₂ signaling

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P₂ signaling

The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1–Sphingosine 1-Phosphate Pathway

Sphingosine Kinase 1 Is a Negative Regulator of CD4+ Th1 Cells

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Sphingosine kinase-1 mediates TNF-α-induced MCP-1 gene expression in endothelial cells: upregulation by oscillatory flow

Cited by 76 publications

References 42 publications

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P2 signaling

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P2 signaling

The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1–Sphingosine 1-Phosphate Pathway

Sphingosine Kinase 1 Is a Negative Regulator of CD4+ Th1 Cells

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Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P₂ signaling

Tumor necrosis factor‐α exerts pro‐myogenic action in C2C12 myoblasts via sphingosine kinase/S1P₂ signaling