title: C6-ceramide enhances Interleukin-12-mediated T helper type 1 cell responses through a cyclooxygenase-2-dependent pathway.
abstract: Ceramides, lipid molecules located predominantly within the plasma membrane of a cell, can function as second messengers, and have been known to carry out a number of cellular functions. T helper type 1 (Th1) immune responses are known to be involved in the cellular immunity, which is crucial in the cancer and allergy immunotherapy. This study was designed to evaluate the effects of ceramides on T helper cell responses and their underlying mechanisms. We demonstrated that a cell-permeable C6-ceramide (C6) together with IL-12 enhanced Th1 cell differentiation, whereas C6 alone had no effects, as demonstrated by the increased populations of IFN-γ expressing CD4(+) T cells and the up-regulation of IFN-γ production from CD4(+) T cells. In contrast, C2-ceramide and long chain ceramides (C16 and C24) did not affect the Th1 responses. C6 treatment was shown to increase the expression of T-bet, a master transcription factor of Th1 responses, in a dose-dependent fashion. Furthermore, C6 increased the expression of cyclooxygenase-2 (COX-2) in CD4(+) T cells. The C6-mediated increase of IFN-γ production and IFN-γ expressing CD4(+) T cell populations were significantly suppressed by a COX-2 specific inhibitor (NS-398) in a dose-dependent manner. T-bet expression was also decreased by NS-398 treatment, thereby indicating that C6 ceramide enhances Th1 responses via a COX-2 dependent pathway. This result demonstrates that C6 may be utilized in therapies for the treatment of immune diseases such cancer and allergy by enhancing the Th1 activity.
authors: Division of Life Sciences, School of Life Sciences and Biotechnology, Korea University, Seoul 136-701, Republic of Korea.
authors: Chin Siang
authors: CS
authors: Kue
authors: Mi Young
authors: MY
authors: Jung
authors: Daeho
authors: D
authors: Cho
authors: Tae Sung
authors: TS
authors: Kim
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D002518:Ceramides / Q000494:pharmacology*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009578:Nitrobenzenes / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D002518:Ceramides; D016861:Cyclooxygenase Inhibitors; C064769:N-acetylsphingosine; D009578:Nitrobenzenes; D013449:Sulfonamides; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; C101954:N-caproylsphingosine; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D018664:Interleukin-12; D007371:Interferon-gamma; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D013110:Sphingosine