Sphingolipids are components of the plasma membrane whose metabolic manipulation is of interest as a potential therapeutic approach in a number of diseases.
Sphingosine kinase 1 (SphK1), the major
kinase that phosphorylates
sphingosine to
sphingosine-1-phosphate (S1P), was previously shown by our group and others to modulate
inflammation in murine models of inflammatory
arthritis,
inflammatory bowel disease and
asthma.
Sphingosine kinase 2's (SphK2) impact on
inflammation is less well known, as variable results were reported depending on the disease model. A specific SphK2 inhibitor inhibited inflammatory
arthritis in one model, while
siRNA knockdown of SphK2 worsened
arthritis in another. We previously demonstrated that SphK1 deficient mice are protected against development of hTNF-α-induced
arthritis. To investigate the role of SphK2 in TNF-α-induced
arthritis, we developed SphK2 deficient hTNF-α overexpressing mice and separately treated hTNF-α mice with
ABC294640, a SphK2-specific inhibitor. Our data show that genetic inhibition of SphK2 did not significantly impact the severity or progression of inflammatory
arthritis, while pharmacologic inhibition of SphK2 led to significantly more severe
arthritis. Compared to vehicle-treated mice,
ABC294640 treated mice also had less S1P in whole blood and inflamed joint tissue, although the differences were not significant.
ABC294640 treatment did not affect SphK1 activity in the inflamed joint while little SphK2 activity was detected in the joint. We conclude that the differences in the inflammatory phenotype in genetic inhibition versus pharmacologic inhibition of SphK2 can be attributed to the amount of
ABC294640 used in the experiments versus the impact of acute inhibition of SphK2 with
ABC294640 versus genetically induced life-long SphK2 deficiency. Thus, inhibition of SphK2 appears to be proinflammatory in contrast to the clear anti-inflammatory effects of blocking SphK1.
Therapies directed at this
sphingosine kinase pathways will need to be specific in their targeting of
sphingosine kinases.