12/10/2009. Department of Pathology, Case Western Reserve University. Mucosal Cytokine Network in IBD

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1 Cytokine-Mediated Inflammation in IBD Theresa T. Pizarro Department of Pathology, Case Western Reserve University Mucosal Cytokine Network in IBD Andoh, et al.,

2 Interleukin-1 (IL-1) Family Cytokine group of ligands and receptors related by mechanisms of origin, receptor structure and common signal transduction pathways Common Name IL-1 Family Name Function Ligand-Binding Chain IL-1α IL-1F1 Agonist IL-1R type I IL-1β IL-1F2 Agonist IL-1R type I IL-1ra IL-1F3 Antagonist IL-1R type I IL-18 IL-1F4 Agonist IL-18R IL-1F5 Agonist IL-1Rrp2 IL-1F6 Agonist IL-1Rrp2 IL-1F7 Unknown IL-18R IL-1F8 Agonist IL-1Rrp2 IL-1F9 Agonist IL-1Rrp2 IL-1F10 Unknown Unknown IL-33 IL-1F11 Agonist ST2 Adapted from Pizarro and Cominelli, J Immunol

3 Charles receives Crafoord Prize from the Royal Swedish National Academy of Sciences awarded by King Carl Gustaf of Sweden, May 11, Albany Medical Center Prize in Medicine and Biomedical Research 2010 Paul Ehrlich and Ludwig Darmstaedter Prize in the Field of Medicine from the Federal Republic of Germany IL-1 family members are synthesized as propeptides and are cleaved into their mature forms by caspase-1, which is activated by the inflammasome Franchi L, Nat Immunol

4 Cominelli et al., J Clin Invest

5 Carter et al., Gut 2001 Casini-Raggi et al., J Immunol 1995 Pizarro et al., J Immunol

6 Pizarro et al., J Imunol 1999 Corbaz et al., J Immunol

7 Interleukin-33 * Interleukin-33 (IL-33) is a novel cytokine, recently recognized as an Interleukin-1 family member (Schmitz J, Immunity 2005) Expression of IL-33 has been shown in several types of cells, both haematopoietic (macrophages, DCs) and nonhaematopoietic (fibroblasts, adipocytes, SMCs, ECs, IECs) (Schmitz J, Immunity 2005) IL-33 is the ligand of the ST2 receptor, which is expressed by Th2 lymphocytes and mast cells, as well as fibroblasts and epithelial cells (Lohning M, PNAS 1998; Xu D, J Exp Med 1998; Tago K, Biochem Biophys Res Commun 2001) 2008 * Adapted from Schmitz J, Immunity 2005 Adapted from Arend WP, Immunol Rev IL-33 isoforms IL-33 was initially thought to be activated by the inflammasome through caspase-1 cleavage of a full-length form (30 kda) in to an active form, similarly to other IL-1 family members, recently it has been demonstrated that : 1) full-length IL-33 is the most bioactive form 2) Caspase-1 activation does not occur during physiological conditions 3) Pro-apoptotic caspases (-3 and -7) cleave IL-33 into less active kda forms Luthi et al., Immunity

8 Role of IL-33 as an alarmin Full-length IL-33 contains a nuclear localization sequence and a DNA-binding domain ; constitutively localized to the nucleus of endothelial and epithelial cells * No clear data regarding ll-33 mechanism of secretion is avalaible; proposed release by suffering/dying cells, acting as a novel alarmin * * Thus, most bioactive IL-33 form (full length) may be released during necrosis, and processed into less potent, cleaved IL-33 during apoptosis Carriere V, PNAS 2007; * Moussion C, PLoS ONE 2008 sst2 IL-33: ligand for ST2 receptor; belongs to the Toll/IL-1R (TIR) superfamily ST2L ST2: expressed by Th2 lymphocytes and mast cells, as well as fibroblasts and epithelial cells 2 different splice variants of ST2 have been described: - ST2L, localized to cell membrane - sst2, soluble form functioning as decoy receptor * Arend WP, Immunol Rev

9 ST2L IL-33 IL-1RAcP ST2L requires the presence of IL- 1RAcP in order to initiates the signaling cascade IL-33/ST2 signaling pathway involves MyD88, p38, JNK, NF-κB and AP-1* MyD88 NF-κB / AP-1 p38 Kakkar et al., Nat Rev Drug Discov 2008 Ali et al., PNAS 2007 Potential role for IL-33 in the gut * IL-33 induces Th2 cytokine production and potentiates both Th1 and Th2 responses exposure to IL-33 in the gut causes epithelial hyperplasia, neutrophil and eosinophil infiltration However, to date, no data regarding IL-33 and ST2 expression and role in IBD are available PB S IL- 33 * Adapted from Kakkar R, Nat Rev Drug Discov 2008 Adapted from Schmitz J, Immunity

10 Features of the SAMP1/YitFc (SAMP) mouse model of experimental Crohn s disease n Spontaneous ileitis without chemical, genetic or immunologic manipulation n 100% penetrance by 12 wks; persistence of phenotype up to 80 wks of age n Closely resembles human CD for disease location and histologic features n Disease mediated by both Th1 and Th2 cytokines n Responsive to standard CD therapies (i.e. steroids, anti-tnf) n Earliest changes are characterized by epithelial cell alterations Full-length IL-33 and sst2 are increased in UC inflamed mucosa A B Pastorelli et al. submitted 10

11 IL-33 is localized to IEC and LPMC in the inflamed mucosa of UC patients UC UC IEC CD UC LPMC CONT UC NEG Pastorelli et al. submitted Immunolocalization of ST2 is altered in intestinal tissue from UC patients U C CD UC IEC CONT CONT IEC UC NEG Pastorelli et al. submitted 11

12 Differential ST2 expression in epithelium of UC vs. inflammatory control patients U C INF COL DI V Pastorelli et al. submitted IL-33 expression is increased and ST2L is downregulated in IEC from UC patients A 16 2 Relative IL-33 mrna expression 8 P<0.05 P<0.05 Relative ST2 mrna expression 1 P< N=18 N=10 N=7 0 N=18 N=10 N=7 B Pastorelli et al. submitted 12

13 IL-33 and sst2 serum levels are significantly increased in IBD patients and cleaved IL-33 is the main circulating form A 2500 P< P<0.05 IL-33 serum levels (pg/ml) P<0.01 sst2 serum levels (pg/ml) P<0.05 P<0.05 IL-33/sST2 Ratio N=59 N=72 N=19 SLD =5 pg/ml 0 N=59 N=72 N=19 SLD =32 pg/m l 0 N=57 N=71 N=19 B Pastorelli et al. submitted ACKNOWLEDGEMENTS Luca Pastorelli Rekha Rani Garg Benedetta Mattioli Sharon Hoang Xiao Ming Wang Maurizio Vecchi University of Milano Claudio Fiocchi Cleveland Clinic Foundation Fabio Cominelli CWRU 13

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