Acid beta-glucosidase 1 counteracts p38delta-dependent induction of interleukin-6: possible role for ceramide as an anti-inflammatory lipid.
Activation of protein kinase C (PKC) by the phorbol ester (phorbol 12-myristate 13-acetate) induces ceramide formation through the salvage pathway involving, in part, acid beta-glucosidase 1 (GBA1), which cleaves glucosylceramide to ceramide. Here, we examine the role of the GBA1-ceramide pathway, in regulating a pro-inflammatory pathway initiated by PKC and leading to activation of p38 and induction of interleukin 6 (IL-6). Inhibition of ceramide formation by fumonisin B1 or down-regulation of PKCdelta potentiated PMA-induced activation of p38 in human breast cancer MCF-7 cells. Similarly, knockdown of GBA1 by small interfering RNAs or pharmacological inhibition of GBA1 promoted further activation of p38 after PMA treatment, implicating the GBA1-ceramide pathway in the termination of p38 activation. Knockdown of GBA1 also evoked the hyperproduction of IL-6 in response to 4beta phorbol 12-myristate 13-acetate. On the other hand, increasing cellular ceramide with cell-permeable ceramide treatment resulted in attenuation of the IL-6 response. Importantly, silencing the delta isoform of the p38 family significantly attenuated the hyperproduction of IL-6. Reciprocally, p38delta overexpression induced IL-6 biosynthesis. Thus, the GBA1-ceramide pathway is suggested to play an important role in terminating p38delta activation responsible for IL-6 biosynthesis. Furthermore, the p38delta isoform was identified as a novel and predominant target of ceramide signaling as well as a regulator of IL-6 biosynthesis.
Kitatani
Kazuyuki
K
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
Sheldon
Kely
K
Anelli
Viviana
V
Jenkins
Russell W
RW
Sun
Ying
Y
Grabowski
Gregory A
GA
Obeid
Lina M
LM
Hannun
Yusuf A
YA
D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002273:Carcinogens / Q000494:pharmacology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D020868:Gene Silencing / Q000502:physiology; D005962:Glucosylceramidase / Q000502:physiology*; D006801:Humans; D007294:Inositol / Q000031:analogs & derivatives / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism*; D048292:Mitogen-Activated Protein Kinase 13 / Q000378:metabolism*; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D002273:Carcinogens; D002518:Ceramides; D015850:Interleukin-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D007294:Inositol; D048292:Mitogen-Activated Protein Kinase 13; D011493:Protein Kinase C; D005962:Glucosylceramidase; C011423:conduritol epoxide; D013755:Tetradecanoylphorbol Acetate