The role of sphingosine 1-phosphate in the TNF-α induction of IL-8 gene expression in lung epithelial cells

Department of Molecular Biology, University of Texas Health Center at Tyler, 11937 US Highway 271 Tyler, TX 75708-3154, USA.
Gene (Impact Factor: 2.08). 05/2007; 391(1-2):150-60. DOI: 10.1016/j.gene.2006.12.011
Source: PubMed

ABSTRACT Tumor necrosis factor-alpha (TNF-alpha) is an important cytokine involved in the pathogenesis of inflammatory diseases of the lung. Interleukin-8 (IL-8), a C-X-C chemokine, is induced by TNF-alpha and initiates injury by acting as a chemoattractant for neutrophils and other immune cells. Although sphingolipids such as ceramide and sphingosine 1-phosphate (S1-P) have been shown to serve as signaling molecules in the TNF-alpha inflammatory response, their role in the TNF-alpha induction of IL-8 gene expression in lung epithelial cells is not known. We investigated the role of sphingolipids in the TNF-alpha induction of IL-8 gene expression in H441 lung epithelial cells. We found that TNF-alpha induced IL-8 mRNA levels by increasing gene transcription, and the stability of IL-8 mRNA was not affected. Exogenous S1-P but not ceramide or sphingosine increased IL-8 mRNA levels and IL-8 secretion. Dimethylsphingosine, an inhibitor of sphingosine kinase, partially inhibited TNF-alpha induction of IL-8 mRNA levels indicating the importance of intracellular increases in S1-P in the IL-8 induction. S1-P induction of IL-8 mRNA was due to an increase in gene transcription, and the stability of IL-8 mRNA was not affected. S1-P induction of IL-8 mRNA was associated with an increase in the binding activity of AP-1 but the activities of NF-kappaB and NF IL-6 were unchanged. S1-P induced the phosphorylation of ERK, p38 and JNK MAPKs. Pharmacological inhibitors of ERK and p38 but not JNK partly inhibited S1-P induction of IL-8 mRNA levels. These data show that increases in the intracellular S1-P partly mediate TNF-alpha induction of IL-8 gene expression in H441 lung epithelial cells via ERK and p38 MAPK signaling pathways and increased AP-1 DNA binding.

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Available from: Vijayakumar Boggaram, Jul 28, 2015
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    • "Evidence that high-density lipoproteins (HDL) inhibit TNF-ainduced adhesion molecule expression, with concomitant inhibition of SphK activity and S1P production, provides further strength to the role of S1P in TNF-a action [28]. In addition, the blockade of SphK1/S1P by either genetic means or pharmaceutical inhibitors has a potent inhibitory effect on TNF-a-induced superoxide production [23], cyclo-oxygenase 2 (COX2) expression and PGE2 formation [29] [30], and other cytokine/chemokine production, such as IL8, IL6, RANTES and MCP-1 [29] [30] [31]. Interestingly, SphK1/S1P is also required for the production of TNF-a in mycobacteriuminfected macrophages [21], allergen-activated mast cells and the anaphylatoxin C5a or LPS-stimulated monocytes and macrophages [32]. "
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