Acid β-glucosidase 1 counteracts p38δ-dependent induction of interleukin-6: Possible role for ceramide as an anti-inflammatory lipid

Kazuyuki Kitatani, Kely Sheldon, Viviana Anelli, Russell W. Jenkins, Ying Sun, Gregory A. Grabowski, Lina M. Obeid, Yusuf A. Hannun

Research output: Contribution to journalArticlepeer-review

43 Citations (Scopus)

Abstract

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 β-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 PKCδ 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 4β 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 δ isoform of the p38 family significantly attenuated the hyperproduction of IL-6. Reciprocally, p38δ overexpression induced IL-6 biosynthesis. Thus, the GBA1-ceramide pathway is suggested to play an important role in terminating p38δ activation responsible for IL-6 biosynthesis. Furthermore, the p38δ isoform was identified as a novel and predominant target of ceramide signaling as well as a regulator of IL-6 biosynthesis.

Original languageEnglish
Pages (from-to)12979-12988
Number of pages10
JournalJournal of Biological Chemistry
Volume284
Issue number19
DOIs
Publication statusPublished - 2009 May 8
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint Dive into the research topics of 'Acid β-glucosidase 1 counteracts p38δ-dependent induction of interleukin-6: Possible role for ceramide as an anti-inflammatory lipid'. Together they form a unique fingerprint.

Cite this