HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nicholas, C. Articles by Doseff, A. I. Search for Related Content PubMed PubMed Citation Articles by Nicholas, C. Articles by Doseff, A. I.

Apigenin Blocks Lipopolysaccharide-Induced Lethality In Vivo and Proinflammatory Cytokines Expression by Inactivating NF-B through the Suppression of p65 Phosphorylation

Courtney Nicholas^2,, Sanjay Batra^2,*, Melissa A. Vargo^2,, Oliver H. Voss, Mikhail A. Gavrilin^*, Mark D. Wewers^*, Denis C. Guttridge^¶, Erich Grotewold and Andrea I. Doseff^3,*,

^* Heart and Lung Research Institute and Division of Pulmonary and Critical Care, Department of Molecular Genetics, Molecular, Cellular, and Developmental Biology Program, Department of Plant Cellular and Molecular Biology and Plant Biotechnology Center, ^¶ Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio 43210

LPS stimulates monocytes/macrophages through the activation of signaling events that modulate the production of inflammatory cytokines. Apigenin, a flavonoid abundantly found in fruits and vegetables, exhibits anti-proliferative and anti-inflammatory activities through poorly defined mechanisms. In this study, we demonstrate that apigenin inhibits the production of proinflammatory cytokines IL-1β, IL-8, and TNF in LPS-stimulated human monocytes and mouse macrophages. The inhibitory effect on proinflammatory cytokine production persists even when apigenin is administered after LPS stimulation. Transient transfection experiments using NF-B reporter constructs indicated that apigenin inhibits the transcriptional activity of NF-B in LPS-stimulated mouse macrophages. The classical proteasome-dependent degradation of the NF-B inhibitor IB was observed in apigenin LPS-stimulated human monocytes. Using EMSA, we found that apigenin does not alter NF-B-DNA binding activity in human monocytes. Instead we show that apigenin, as part of a non-canonical pathway, regulates NF-B activity through hypophosphorylation of Ser536 in the p65 subunit and the inactivation of the IKK complex stimulated by LPS. The decreased phosphorylation on Ser536 observed in LPS-stimulated mouse macrophages treated with apigenin was overcome by the over-expression of IKKβ. In addition, our studies indicate that apigenin inhibits in vivo LPS-induced TNF and the mortality induced by lethal doses of LPS. Collectively, these findings suggest a molecular mechanism by which apigenin suppresses inflammation and modulates the immune response in vivo.

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 work was supported by Grant R01 HL075040–01 and NSF-MCB-0542244 (to A.I.D.); National Research Initiative of the USDA Cooperative State Research, Education and Extension Service, Grant 2002-35301-12028 (to E.G.)

² C.N., S.B., and M.A.V. equally shared first authorship.

³ Address correspondence and reprint requests to Dr. Andrea I. Doseff, 201 Davis Heart and Lung Research Institute, Molecular Genetics, Ohio State University, 473 West 12th, Columbus, OH 43210. E-mail address: Doseff.1{at}osu.edu

⁴ Abbreviations used in this paper: IKK, IB-kinase complex; PKC, protein kinase C; RCN, relative copy number.

This article has been cited by other articles:

				J. Waak, S. S. Weber, A. Waldenmaier, K. Gorner, M. Alunni-Fabbroni, H. Schell, D. Vogt-Weisenhorn, T.-T. Pham, V. Reumers, V. Baekelandt, et al. Regulation of astrocyte inflammatory responses by the Parkinson's disease-associated gene DJ-1 FASEB J, August 1, 2009; 23(8): 2478 - 2489. [Abstract] [Full Text] [PDF]

				Y. Hong, C. Huang, S. Wang, and B. Lin The ethyl acetate extract of alfalfa sprout ameliorates disease severity of autoimmune-prone MRL-lpr/lpr mice Lupus, March 1, 2009; 18(3): 206 - 215. [Abstract] [PDF]

				P. Kaur, S. Shukla, and S. Gupta Plant flavonoid apigenin inactivates Akt to trigger apoptosis in human prostate cancer: an in vitro and in vivo study Carcinogenesis, November 1, 2008; 29(11): 2210 - 2217. [Abstract] [Full Text] [PDF]

				Y. Zhang, S. Saccani, H. Shin, and B. S. Nikolajczyk Dynamic Protein Associations Define Two Phases of IL-1{beta} Transcriptional Activation J. Immunol., July 1, 2008; 181(1): 503 - 512. [Abstract] [Full Text] [PDF]