The two lives of Interleukin-33: in- and outside of cells

Il 27/05/2016 ore 14.30 - 15.30

Sala Conferenze Cnr, Via P. Castellino,111 80131 Napoli

Michael U. Martin from Justus-Liebig-University Giessen, Germany, will give a seminar on Interleukin-33 (IL-33, a member of the IL-1 family of pro-inflammatory cytokines which is involved in organizing innate and adaptive immune responses. It shares many features with its cousins IL-1α, IL-1β, and IL-18, however, it also shows some peculiarities which deserve attention. Unlike most of the IL-1 family members, IL-33 is not predominantly produced and released by (stimulated) leukocytes, but is constitutively expressed by cells involved in maintaining mechanical barriers such as epithelial and endothelial cells. In the cells producing IL-33 it is found almost exclusively in the nucleus, where it exerts gene regulatory functions by different mechanisms. These cells do not release IL-33, thus nuclear IL-33 is regarded as a stored alarmin and functions as a guardian of barriers. Regulation of intracellular IL-33 activities by post-translational modifications will be discussed.

If the barrier is breached and IL-33 is liberated after injury or necrosis of cells, but not after apoptosis, it acts as a damage-associated molecular pattern to induce (sterile) inflammation. This “cytokine” function of IL-33 is strictly dependent on the IL-33 receptor and IL-33 can, but does not have to be, processed to be biologically active.

Free IL-33 binds to a specific plasma membrane receptor complex, minimally consisting of the IL-33 receptor α-chain (IL-1R4, formally known as ST2/T1/Fit-1/Der-4) and the common β-chain of the IL-1 receptor family, IL-1RAcP (IL-1R3 also known as IL-1 receptor accessory protein). Upon formation of the signaling IL-33 receptor complex, the two TIR-domains of the transmembrane receptor components associate and form a scaffold to which the MyD88/IRAK/TRAF-6 signaling module of the TLR and IL-1R families is recruited, Thus IL-33 activates the typical intracellular signaling mechanisms known for IL-1, e.g. resulting in the activation of the transcription factors NF-κB and AP-1 leading to a pro-inflammatory gene activation profile. However, in mast cells, the IL-33R complex may be more complicated involving the receptor tyrosine kinase c-Kit, which cross talks with IL-33 signaling resulting in an additional layer of regulation of IL-33 responsiveness. Possible mechanisms how this crosstalk may be organized on a molecular level will be discussed.

After studying biochemistry at the University of Hannover, Germany, he finished his Diploma thesis in 1984 and started to work on inflammation in his PhD thesis in the pharmacology department of the Hannover Medical School. He finished his thesis on Interleukin-1 as Dr. rer. nat. in 1986. After a brief period from 1987 to 1989 as head of a research laboratory at BASF AG, Ludwigshafen in Biotechnology, Immunology/Oncology he spent two years as a DFG-sponsored Postdoctoral Research Fellow at The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia where he worked on hematopoietic factors. From 1992 till 2002 he was a senior research fellow in the Institute for Clinical Molecular Pharmacology at the Hannover Medical School, were he was head of the clinical immunopharmacology group. In 1994 he obtained the venia legendi for immunology (Habilitation). Since January 2003 he is full professor for immunology in the faculty of biology and chemistry at the Justus-Liebig-University Giessen in Germany. His main research interest remains in immunopharmacology especially chronic inflammatory diseases. A special emphasis is the investigation of the Interleukin-1 family of cytokines, their receptors and signalling mechanisms as potential novel pharmacological targets for anti-inflammatory intervention strategies.

Organizzato da:
IBP, Cnr

Referente organizzativo:
Diana Boraschi
CNR - Istituto di biochimica delle proteine
d.boraschi@ibp.cnr.it
081/6132623

Modalità di accesso: ingresso libero