Regulation of IL-6 signal transduction, contributions of the Signal Regulatory Protein (SIRP) and cyclic AMP

The transmembrane glycoprotein “signal regulatory protein/SHP-substrate” (SIRP alpha/SHPS-1) has been implicated in growth factor- and cell adhesion-induced signalling. In the first part of this thesis it is shown for the first time that SIRP alpha contributes to IL-6-type cytokine signalling. SIRP alpha binds to the protein tyrosine phosphatase SHP2 upon IL-6 stimulation. Mouse embryonal fibroblasts which express a SIRP alpha protein lacking the intracellular part show an enhanced SHP2 phosphorylation and ERK1/2 activation in response to IL-6, suggesting that SIRP alpha affects IL-6-signalling through SHP2. Whereas SHP2 phosphorylation is enhanced in SIRP aplha-deficient cells STAT3 activation is delayed and STAT3-dependent gene induction is reduced. In the second part of this thesis an experimental system was set up to analyse whether signalling through G-protein-coupled receptors has a regulatory function on IL-6-induced signal transduction. Activation of adenylate cyclase or a block of its inhibition by pertussis toxin (PTX) was found to counteract IL-6-induced ERK-activation, but not STAT3 tyrosine phosphorylation in normal human dermal fibroblasts (NHDF). The same observation was made in NHDF cells stimulated with prostaglandin E1 (PGE1), known to activate adenylate cyclase. Furthermore, with the help of specific prostagalndin EP2 receptor agonist (R-butaprost), a receptor mediated PGE1-dependent ERK inhibition was identified. Protein kinase A (PKA) activated by cAMP was shown to trigger ERK inhibition. In addition, c Raf 1 was identified to be a target of PKA in the Raf/MEK/ERK cascade in NHDF cells. PGE1-mediated inhibition of IL-6 signalling was reflected in decrease IL-6 induced chemokine MCP-1 expression in fibroblasts. In summary, in this thesis a specific crosstalk between the adenylate cyclase cascade-activated through G-protein-coupled receptors and the IL-6-induced MAPK signalling was discovered. In addition a positive effect of SIRP alpha on IL-6 dependent gene induction was elaborated. These results advanced the knowledge about the molecular mechanisms involved in the regulation of IL-6 signalling during inflammatory processes.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2007

Author dc:creator

• Sobota, Radoslaw Mikolaj

Contributors dc:contributor

• Heinrich, Peter C.

• info:eu-repo/classification/ddc/610
• Cyclo-AMP
• Interleukin 6
• Prostaglandin E1
• MAP-Kinase
• STAT
• Medizin
• SIRP
• SHP2
• IL-6
• cAMP
• PGE1
• MAPK

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-124075%22

OAI identifier oai:identifier

oai:publications.rwth-aachen.de:62509