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B in Primary Human Astrocytes via Acetylation of p651
,*,*
* Department of Neurological sciences, Rush University Medical Center, Chicago, IL 60612; and
Section of Neuroscience, Department of Oral Biology, University of Nebraska Medical Center, Lincoln, NE 68583
MAPK-p38 plays an important role in inflammation. Several studies have shown that blocking p38 activity attenuates the transcriptional activity of the proinflammatory transcription factor NF-
B without altering its DNA-binding activity. We have also observed that blocking p38 in human primary astrocytes suppresses the transcriptional but not the DNA-binding activity of NF-B and down-regulates the expression of an NF-B-dependent gene, inducible NO synthase. However, the molecular mechanism of p38-mediated regulation of NF-B remains largely unknown. In this study, we delineate that p38 controls the transcriptional activity of NF-B by regulating acetylation of p65, but not its phosphorylation. The combination of IL-1β and IFN-
, previously shown to strongly induce inducible NO synthase in human primary astrocytes, induced p38-dependent phosphorylation of acetyltransferase coactivator p300, but not p65, and subsequent association of p300 with p65. Furthermore, immunocomplex-histone acetyltransferase assays demonstrated that cytokine-induced association of p65 with biologically active immunocomplex-histone acetyltransferase assay was dependent on p38. It has been previously reported that acetylation of p65 at K310 residue is important for transcriptional activity of NF-B. Accordingly, we found that cytokine-induced association of p65 with p300 led to acetylation of p65 at K310. Because p38 regulated the association between p65 and p300, blocking p38 activity also led to attenuation of p65-K310 acetylation in cytokine-stimulated astrocytes. Taken together, this study illuminates a novel regulatory role of p38 during neuroinflammation where this MAP kinase controls acetylation of NF-B p65 by regulating acetyltransferase activity of coactivator p300.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by grants from NIH (NS39940 and NS48923), National Multiple Sclerosis Society (RG3422A1/1), and Michael J. Fox Foundation for Parkinson’s research.
2 Current address: Laboratory of Neurobiology, MD F2-04, National Institute on Environmental Health Sciences, National Institutes of Health, 111 T.W. Alexander Drive, Research Triangle Park, NC 27709
3 Address correspondence and reprint requests to Dr. Kalipada Pahan, Department of Neurological Sciences, Rush University Medical Center, Cohn Research Building, Suite 320, 1735 West Harrison Street, Chicago, IL 60612. E-mail address: Kalipada_Pahan{at}rush.edu
4 Abbreviations used in this paper: iNOS, inducible NO synthase; hr, human recombinant; siRNA, short interfering RNA; DAPI, 4',6'-diamidino-2-phenylindole; HAT, histone acetyltransferase; MSK1, mitogen- and stress-activated protein kinase 1; CBP, CREB-binding protein.
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