Multiple control of interleukin-8 gene expression.
Interleukin (IL)-8, a prototypic human chemokine, was detected more than a decade ago as the founding member of the chemokine superfamily. One of the most remarkable properties of IL-8 is the variation of its expression levels. In healthy tissues, IL-8 is barely detectable, but it is rapidly induced by ten- to 100-fold in response to proinflammatory cytokines such as tumor necrosis factor or IL-1, bacterial or viral products, and cellular stress. Recently, significant advances in the understanding of signaling pathways, which coordinately regulate IL-8 transcription as well as mRNA stabilization in response to external stimuli, have been made. Maximal IL-8 amounts are generated by a combination of three different mechanisms: first, derepression of the gene promoter; second, transcriptional activation of the gene by nuclear factor-kappaB and JUN-N-terminal protein kinase pathways; and third, stabilization of the mRNA by the p38 mitogen-activated protein kinase pathway. In that way, cells are able to rapidly increase and at the same time, to fine-tune the amount of IL-8 secreted and thereby control the extent of leukocytes attracted to sites of tissue injury.
Hoffmann
Elke
E
Institute of Pharmacology, Medical School Hannover, Germany.
Dittrich-Breiholz
Oliver
O
Holtmann
Helmut
H
Kracht
Michael
M
D000818:Animals; D001483:Base Sequence; D004268:DNA-Binding Proteins; D005786:Gene Expression Regulation; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000235:genetics*; D020930:MAP Kinase Kinase Kinases / Q000502:physiology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism; D020871:RNA Stability; D012097:Repressor Proteins / Q000502:physiology; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D016209:Interleukin-8; D016328:NF-kappa B; C111027:NKRF protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; D020928:Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases