Attenuation of interferon-gamma mRNA expression in activated Jurkat T cells by exogenous zinc via down-regulation of the calcium-independent PKC-AP-1 signaling pathway.
Zinc is known to modulate a wide variety of cellular functions including anti-inflammatory responses. We examined the intracellular signaling pathways that contribute to the regulation of interferon-gamma (IFN-gamma) by zinc in activated human Jurkat T cells. Zinc significantly reduced IFN-gamma expression and activator protein-1 (AP-1) signaling in cells activated by phorbol 12-myristate 13-acetate (PMA) and phytohemagglutinin (PHA) without affecting cell viability. Moreover, partial inhibition of AP-1 activity by SP600125, a c-Jun N-terminal kinase (JNK) inhibitor, resulted in marked reduction of IFN-gamma transcription. We also found that this inhibitory effect of zinc on AP-1 signaling was abolished by treatment with rottlerin, a selective inhibitor of calcium-independent protein kinase C (PKC). These results suggest a novel target of zinc in the calcium-independent protein kinase C-AP-1 pathway to regulate endogenous IFN-gamma gene expression in activated T cells.
Department of Pharmacology, National Cardiovascular Center Research Institute, 5-7-1, Fujishiro-dai, Suita, Osaka 565-8565, Japan. kumizaru-5@umin.net
Kumiko
K
Hayashi
Satoshi
S
Ishizuka
Chieko
C
Yokoyama
Toshihisa
T
Hatae
D015536:Down-Regulation; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000378:metabolism*; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors*; D015032:Zinc / Q000494:pharmacology*
D012333:RNA, Messenger; D018808:Transcription Factor AP-1; D007371:Interferon-gamma; C115197:calcium-independent protein kinase C; D011493:Protein Kinase C; D015032:Zinc