Regulation of suppressor of cytokine signalling 3 expression by the pro-inflammatory cytokine (IL-1beta) in vitro and inflammatory stimuli in vivo

Interleukin-6 (IL-6) exerts pro- as well as anti-inflammatory activities in response to infection, injury or other stimuli which affect the homeostasis of the organism. IL-6-induced expression of acute phase protein genes in the liver is tightly regulated through both IL-6-induced feedback inhibitors and the activity of pro-inflammatory cytokines such as tumor necrosis factor alpha and interleukin-1beta. In previous studies mechanisms of how IL-1beta counteracts IL-6-dependent acute phase protein gene induction have been proposed. Apart from negatively regulating the IL-6-type cytokine signalling pathways, SOCS3 is also essential for regulating many immunological processes. In the first part of this thesis, we analyzed how IL-1beta regulates IL-6-induced SOCS3 expression. In hepatocytes IL-1beta alone does not induce SOCS3 expression but it counteracts SOCS3-promoter activation in long term studies (>3h). Surprisingly, short term stimulation (around 50 minutes) revealed IL-1beta to be a potent enhancer of SOCS3 expression in concert with IL-6. This activity of IL-1beta depends neither on IL-1beta-induced p38 MAPKs activity nor on IL-1beta-dependent STAT1-serine phosphorylation, but on NF-kappaB-mediated gene induction. Most importantly, we found IL-6-induced SOCS3 mRNA to be stabilized by the signal propagated from IL-1beta. Such a regulatory network allows IL-1beta to counteract IL-6-dependent expression of acute phase protein genes without inhibiting IL-6-induced SOCS3 expression. Moreover, it provides a sophisticated mechanism for the IL-1beta-dependent inhibition of acute phase protein gene induction since reduced SOCS3 expression would lead to enhanced IL-6 activity.Several signalling pathways have been shown to converge on SOCS3, thereby allowing an extensive cross-talk. However, the individual contribution of each cytokine to the induction of SOCS3 during the inflammatory processes in vivo is not clear. Using IL-6-deficient mice in two well-established animal models of bacterial (LPS) and aseptic (turpentine) inflammation, a central role of IL-6 on hepatic expression of SOCS3 during inflammatory processes was uncovered and is described in the second part of this thesis.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2005

Author dc:creator

• Yang, Xiangping

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/610
• Medizin
• Interleukin
• SOCS
• Entzündung
• Genexpression
• inflammation
• gene expression

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-123760%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62170