title: Lysophosphatidic acid enhances interleukin-13 gene expression and promoter activity in T cells.
abstract: Lysophosphatidic acid (LPA) is a membrane-derived lysophospholipid with wide-ranging effects on multiple lung cells including airway epithelial and smooth muscle cells. LPA can augment migration and cytokine synthesis in lymphocytes, but its potential effects on Th2 cytokines have not been well studied. We examined the effects of physiological concentrations of LPA on IL-13 gene expression in human T cells. The Jurkat T cell line and human peripheral blood CD4+ T cells were incubated with LPA alone or with 1) pharmacological agonists of different signaling pathways, or 2) antibodies directed against the T cell receptor complex and costimulatory molecules. Luciferase-based reporter constructs driven by different lengths of the human IL-13 promoter were transfected by electroporation in Jurkat cells treated with and without LPA. The effects of LPA on IL-13 mRNA stability were examined using actinomycin D to halt ongoing transcription. Expression of mRNA encoding LPA2 and LPP-1 increased with T cell activation. LPA augmented IL-13 secretion under conditions of submaximal T cell activation. This was observed using pharmacological agonists activating intracellular calcium-, PKC-, and cAMP-dependent signaling pathways, as well as antibodies directed against CD3 and CD28. LPA only slightly prolonged IL-13 mRNA half-life in submaximally stimulated Jurkat cells. In contrast, LPA significantly enhanced transcriptional activation of the IL-13 promoter via regulatory elements contained within proximal 312 bp. The effects of LPA on IL-13 promoter activation appeared to be distinct from those mediated by GATA-3. LPA can augment IL-13 gene expression in T cells, especially under conditions of submaximal activation.
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland 21224, USA.
authors.forename: Joshua
authors.initials: J
authors.lastname: Rubenfeld
authors.forename: Jia
authors.initials: J
authors.lastname: Guo
authors.forename: Nitat
authors.initials: N
authors.lastname: Sookrung
authors.forename: Rongbing
authors.initials: R
authors.lastname: Chen
authors.forename: Wanpen
authors.initials: W
authors.lastname: Chaicumpa
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Casolaro
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Viswanathan
authors.initials: V
authors.lastname: Natarajan
authors.forename: Steve
authors.initials: S
authors.lastname: Georas
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D000001:Calcimycin / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism*; D007476:Ionophores / Q000494:pharmacology; D019169:Jurkat Cells; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects*; D020033:Protein Isoforms / Q000378:metabolism; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018793:Interleukin-13; D007476:Ionophores; D008246:Lysophospholipids; D020033:Protein Isoforms; D000001:Calcimycin; C032881:lysophosphatidic acid