Ovalbumin-induced plasma interleukin-4 levels are reduced in ceramide kinase-deficient DO11.10 RAG1-/- mice

Abstract

Ceramide kinase (CERK) produces the bioactive lipid ceramide-1-phosphate (C1P) and is a key regulator of ceramide and dihydroceramide levels. It is likely that CERK and C1P play a role in inflammatory processes but the cells involved and the mechanisms used remain to be clarified. In particular, the impact of CERK on T-cell biology has not been studied so far. Here, we used Cerk-/- mice backcrossed with DO11.10/RAG1-/- mice to probe the effect of CERK ablation on T-cell activation. Levels of interleukin (IL)-2, IL-4, IL-5, IL-13, of tumor necrosis factor (TNF)-α, and of interferon (INF)-γ were recorded following ovalbumin challenge in vivo and using ovalbumin-treated splenocytes ex- vivo. Absence of CERK led to a significant decrease in the production of IL-4, thus suggesting that CERK may polarize T cells towards the TH2 cell subtype. However, the importance of CERK to TH2 cell biology will have to be investigated further because in a model of asthma, which is TH2-cell driven, Cerk-/- mice responded like wild-type animals.

Characterization of eicosanoid synthesis in a genetic ablation model of ceramide kinase

“…This further illustrates the effects of CERK-derived C1P on eicosanoid production, and therefore implicates these mediators as players in the infl ammatory response. Of note, these fi ndings are partially in opposition to the reports by Bornancin and coworkers ( 23,24,49 ). Specifi cally, this group explored how cPLA 2 ␣ -dependent pathways were affected by the genetic ablation of CERK and this laboratory observed similar responses of cells derived from both wild-type and knockout animals to PMA/ionomycin treatment as well as the susceptibility of the whole animals to arthritis induction by both Ag and KRN serum.…”

“…There have been reports of few phenotypes in the CERK Ϫ / Ϫ mice (23)(24)(25) in comparison to phenotypes found in the cPLA 2 ␣ knockout mice (37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48), which is unexpected given the importance of the binding of C1P and cPLA 2 ␣ in the activation of the enzyme and resulting eicosanoid synthesis ( 15 ). This lack of phenotypes suggests the possibility that the CERK Ϫ / Ϫ mice may have at least partially adapted to the loss of CERK.…”

“…For example, Graf et al ( 23 ) found that the CERK Ϫ / Ϫ animals were sensitive to both antigen (Ag)-induced and serum transfer-induced arthritis in contrast to the cPLA 2 ␣ knockout suggesting that cPLA 2 ␣ pathways are fully functional in the CERK Ϫ / Ϫ animals. In contrast, this same laboratory group reported that basal prostaglandin E 2 (PGE 2 ) synthesis was reduced in the bronchoalveolar (BAL) fl uid of CERK Ϫ / Ϫ mice ( 24 ). Importantly, these studies showed an appreciable amount of D-e-C 18:1/16:0 C1P was still present in the CERK Ϫ / Ϫ cells, and other C1P subspecies were not characterized.…”

“…Furthermore, DAGK has high homology to more recent report using a specifi c CERK inhibitor (NVP-231) in vitro ( 49 ). In regards to the CERK Ϫ / Ϫ mice, this genetic ablation model does not demonstrate the phenotypes observed in the cPLA 2 ␣ knockout mice (e.g., resistance to arthritis induction by both Ag and KRN serum and OVA-induced AHR) with the exception of one report by Bornanicin and coworkers showing a reduction in the levels of basal PGE 2 in the BAL fl uid of the CERK Ϫ / Ϫ mice ( 23,24 ). As a decade of research from our laboratory and others has shown cPLA 2 ␣ to possess a specifi c C1P interaction site, we hypothesized that the CERK Ϫ / Ϫ mice were able to demonstrate intact cPLA 2 ␣ -dependent pathways due to an adaptation of the whole mouse to the loss of CERK-derived C1P ( 15-20, 22, 33-35 ).…”

Ceramide-1-phosphate inhibits cigarette smoke-induced airway inflammation

“…The central molecule ceramide triggers apoptosis of pulmonary epithelial cells, and increased pulmonary levels of ceramide lead to the development of emphysema in mice [5,7]. Furthermore, elegant in vitro and in vivo experiments emphasise that ceramide and its derivatives modulate chronic pulmonary inflammation in bronchial asthma [8,9] and cystic fibrosis [6]. Ceramide is de novo generated by serine palmitoyl transferase, ceramide synthase or via membrane sphingomyelin hydrolysis by sphingomyelinase (SMase).…”