Normal acute and chronic inflammatory responses in sphingosine kinase 1 knockout mice

Michaud, Jason; Kohno, Masataka; Proia, Richard L.; Hla, Timothy

doi:10.1016/j.febslet.2006.07.035

Cited by 79 publications

(61 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…SphK1 expression is increased in human IBD colons, and SphK1-deficient mice are protected from IBD pathology (14). These are in contrast to data generated from models of thioglycollate-induced peritonitis and CIA, where SphK1 knockout mice exhibit normal acute and chronic inflammatory responses (31). It is possible that mice lacking the SphK1 gene during embryonic development may be adapted not to rely on this pathway for inflammatory responses postnatally.…”

Section: Discussioncontrasting

confidence: 52%

Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis

Lai

Irwan

Goh

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

Sphingosine kinase (SphK) phosphorylates sphingosine into sphingosine-1-phosphate (S1P). S1P plays a critical role in angiogenesis, inflammation, and various pathologic conditions. To date, two mammalian isoenzymes, SphK1 and SphK2, have been identified. Although both SphK1 and SphK2 share overall homology and produce the common product, S1P, it has been proposed they display different unique and separate functions. In this study, we examined the role of SphK1 and SphK2 in a murine collagen-induced arthritis model by down-regulating each isoenzyme via specific small interfering RNA (siRNA). Prophylactic i.p. administration of SphK1 siRNA significantly reduced the incidence, disease severity, and articular inflammation compared with control siRNA recipients. Treatment of SphK1 siRNA also down-regulated serum levels of S1P, IL-6, TNF-α, IFN-γ, and IgG2a anti-collagen Ab. Ex vivo analysis demonstrated significant suppression of collagen-specific proinflammatory/Th1 cytokine (IL-6, TNF-α, IFN-γ) release in SphK siRNA-treated mice. Interestingly, mice received with SphK2 siRNA develop more aggressive disease; higher serum levels of IL-6, TNF-α, and IFN-γ; and proinflammatory cytokine production to collagen in vitro when compared with control siRNA recipients. Together, these results demonstrate the distinct immunomodulatory roles of SphK1 and SphK2 in the development of inflammatory arthritis by regulating the release of proinflammatory cytokines and T cell responses. These findings raise the possibility that drugs which specifically target SphK1 activity may play a beneficial role in the treatment of inflammatory arthritis.

show abstract

Section: Discussioncontrasting

confidence: 52%

Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis

Lai

Irwan

Goh

et al. 2009

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…administration of SphK1 siRNA significantly reduced both incidence and disease severity in the development of murine CIA. Recently, it was suggested that SphK1 knockout mice developed CIA with normal incidence and severity (47). It is possible that mice lacking the SphK1 gene during embryonic development may be adapted to not rely on this pathway for inflammatory responses postnatally.…”

Section: Discussionmentioning

confidence: 99%

Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

Lai

Irwan

Goh

et al. 2008

The Journal of Immunology

119

126

View full text Add to dashboard Cite

Sphingosine kinase (SphK) is a key enzyme in the sphingolipid metabolic pathway responsible for phosphorylating sphingosine into sphingosine-1-phosphate (S1P). SphK/S1P play a critical role in angiogenesis, inflammation, and various pathologic conditions. Recently, S1P1 receptor was found to be expressed in rheumatoid arthritis (RA) synovium, and S1P signaling via S1P1 enhances synoviocyte proliferation, COX-2 expression, and prostaglandin E2 production. Here, we examined the role of SphK/S1P in RA using a potent SphK inhibitor, N,N-dimethylsphingosine (DMS), and a molecular approach against one of its isoenzymes, SphK1. We observed that levels of S1P in the synovial fluid of RA patients were significantly higher than those of osteoarthritis patients. Additionally, DMS significantly reduced the levels of TNF-α, IL-6, IL-1β, MCP-1, and MMP-9 in cell-contact assays using both Jurkat-U937 cells and RA PBMCs. In a murine collagen-induced arthritis model, i.p. administration of DMS significantly inhibited disease severity and reduced articular inflammation and joint destruction. Treatment of DMS also down-regulated serum levels IL-6, TNF-α, IFN-γ, S1P, and IgG1 and IgG2a anti-collagen Ab. Furthermore, DMS-treated mice also displayed suppressed proinflammatory cytokine production in response to type II collagen in vitro. Moreover, similar reduction in incidence and disease activity was observed in mice treated with SphK1 knock-down via small interfering RNA approach. Together, these results demonstrate SphK modulation may provide a novel approach in treating chronic autoimmune conditions such as RA by inhibiting the release of pro-inflammatory cytokines.

show abstract

“…In this context, Zemann et al (2006) reported that serum S1P levels in SK-2-deficient mice increased, but decreased by approximately 50% in SK-1-deficient mice. Moreover, Michaud et al (2006) measured S1P levels in forepaw tissue and found only slight decreases in SK-1-deficient mice. Recently, Mizugishi et al (2007) generated SphK1 -/-SphK2 q/-mice and investigated uterine decidualisation.…”

Section: Discussionmentioning

confidence: 99%

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Hofmann

Ren

Schwalm

et al. 2008

BCHM

View full text Add to dashboard Cite

Sphingosine kinases (SKs) are key enzymes regulating the production of sphingosine-1-phosphate (S1P), which determines important cell responses including cell growth and death. Here we show that renal mesangial cells isolated from wild-type, SK-1 -/-, and SK-2 -/-mice show a differential response to apoptotic stimuli. Wildtype mesangial cells responded to staurosporine with increased DNA fragmentation and caspase-3 processing, which was enhanced in SK-1 -/-cells. In contrast, SK-2 -/-cells were highly resistant to staurosporine-induced apoptosis. Furthermore, the basal phosphorylation and activity of the anti-apoptotic protein kinase B (PKB) and of its substrate Bad were decreased in SK-1 -/-but not in SK-2 -/-cells. Upon staurosporine treatment, phosphorylation of PKB and Bad decreased in wild-type and SK-1 -/-cells, but remained high in SK-2 -/-cells. In addition, the anti-apoptotic Bcl-X L was significantly upregulated in SK-2 -/-cells, which may further contribute to the protective state of these cells. In summary, our data show that SK-1 and SK-2 have opposite effects on the capacity of mesangial cells to resist apoptotic stimuli. This is due to differential modulation of the PKB/Bad pathway and of Bcl-X L expression. Thus, subtype-selective targeting of SKs will be critical when considering these enzymes as therapeutic targets for the treatment of inflammation or cancer.

show abstract

Normal acute and chronic inflammatory responses in sphingosine kinase 1 knockout mice

Cited by 79 publications

References 32 publications

Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis

Distinct Roles of Sphingosine Kinase 1 and 2 in Murine Collagen-Induced Arthritis

Anti-Inflammatory Effects of Sphingosine Kinase Modulation in Inflammatory Arthritis

Sphingosine kinase 1 and 2 regulate the capacity of mesangial cells to resist apoptotic stimuli in an opposing manner

Contact Info

Product

Resources

About