Interleukin-6 and CAAT/enhancer binding protein beta-deficient mice act as tools to dissect the IL-6 signalling pathway and IL-6 regulation.
Interleukin-6 (IL-6) is a pleiotropic cytokine playing important roles in immunity, hemopoiesis and inflammation. IL-6 signalling is known to involve the activation of two independent transcription factors: Stat3 (through phosphorylation by Jak kinases) and C/EBP beta (through activation of the ras pathway). In addition, C/EBP beta is believed to act as a transcriptional activator of the IL-6 gene itself. Making use of IL-6-deficient mice, we have recently demonstrated that IL-6 is essential for the induction of acute phase mRNAs in the liver upon localized tissue damage, but not upon systemically induced inflammation. Here we show that the defective mRNA induction is paralleled by a defective activation of Stat3, thus establishing a direct relationship between IL-6 function, Stat3 activation and acute phase genes induction. On the other hand, making use of C/EBP beta-deficient mice, we show that the induction of IL-6 by a variety of stimuli does not require C/EBP beta activity. In contrast to the predicted activating role of C/EBP beta, IL-6 levels are increased in the C/EBP beta-deficient mice, suggesting that C/EBP beta may act as a down-modulator of the IL-6 gene. Through the generation of C/EBP beta, IL-6 double mutant mice we show that IL-6 hyperproduction is responsible for the development of the Castleman's like lymphoproliferative disease described in the C/EBP beta-deficient mice, since the disorder is completely blocked by inactivating the IL-6 gene.
Alonzi
T
T
Istituto di Ricerche di Biologia Molecolare P. Angeletti (IRBM), Pomezia, Italy.
Gorgoni
B
B
Screpanti
I
I
Gulino
A
A
Poli
V
V
D000210:Acute-Phase Reaction; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins; D005871:Castleman Disease / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha