Emerging cytokines and cytokine signalling molecules as ...
Emerging cytokines and cytokine signalling molecules as ...
Emerging cytokines and cytokine signalling molecules as ...
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<strong>Emerging</strong> <strong><strong>cytokine</strong>s</strong> <strong>and</strong> <strong>cytokine</strong><br />
signaling <strong>molecules</strong> <strong>as</strong> targets in<br />
Psori<strong>as</strong>is<br />
Miriam Wittmann
• Regulation of Inflammation<br />
• Cytokine network in Psoriatic Inflammation<br />
• Mechanical Stress <strong>and</strong> Cytokines<br />
• Kin<strong>as</strong>e Inhibitors<br />
• Outlook
Regulation of immune responses<br />
pro-inflammatory „immune response“<br />
trigger<br />
Inflammation<br />
Resolution<br />
time
Regulation of immune responses<br />
pro-inflammatory „immune response“<br />
trigger<br />
Inflammation<br />
Resolution<br />
1. Persistence of trigger<br />
2. Dysregulated cell activation /<br />
positive feedback<br />
mechanisms<br />
3. Lack of counter-regulatory<br />
pathways<br />
time
Tissue cells<br />
Chemokines:<br />
MCP-1<br />
IL-8<br />
CCL20<br />
Tissue cells<br />
VEGF<br />
IL-1<br />
TNF<br />
IL-6<br />
DAMPs
Koebner phenomenon
McGonagle D, JEADV 2009
Tenocytes<br />
Schulze-Tanzil et al.
Anti-<strong>cytokine</strong> therapies developed for psori<strong>as</strong>is<br />
CT637<br />
HMGB1-RAGE interaction<br />
Generic name<br />
Cytokine Target<br />
Etanercept, Infliximab, Adalimumab TNF<br />
Ustekinumab<br />
Briakinumab<br />
------<br />
Secukinumab<br />
Brodalumab<br />
Ixekizumab<br />
CNTO1959<br />
SCH900222<br />
Fezakinumab (ILV-094)<br />
NN8226<br />
IL12/23 p40<br />
IL12/23 p40 (withdrawn)<br />
IL-17<br />
IL-17<br />
IL-17<br />
IL-23p19<br />
IL-23p19<br />
IL-22<br />
IL-20<br />
AMG 714<br />
IL-15<br />
ABX-IL8 IL-8 (modest results in ph<strong>as</strong>e 2,<br />
MEDI 545<br />
discontinued for psori<strong>as</strong>is)<br />
IFNalpha (ph<strong>as</strong>e 1 completed, no<br />
clinical activity in established dise<strong>as</strong>e)
Tissue cells<br />
Chemokines:<br />
MCP-1<br />
IL-8<br />
CCL20<br />
Tissue cells<br />
VEGF<br />
IL-1<br />
TNF<br />
IL-6<br />
DAMPs
IL-12/IL-23p40<br />
Bell et al, Nat Rev Rheumatol, 2011
IL-17 <strong>and</strong> TNF act synergistically<br />
+ Stromal cells<br />
MMPs<br />
Chiricozzi, J Invest Dermatol, 2011
IL-17 <strong>and</strong> TNF act synergistically<br />
+ Stromal cells<br />
MMPs<br />
Chiricozzi, J Invest Dermatol, 2011
Mechanical Stress <strong>and</strong> Cytokines<br />
IL-36
IL-17 stimulates Psori<strong>as</strong>is-Keratinocytes to express<br />
IL-1F9 (= IL-36)<br />
IL-1F6 (fold induction)<br />
4h<br />
24h<br />
4h<br />
24h<br />
4h<br />
24h<br />
4h<br />
24h<br />
IL-1F9 (fold induction)<br />
IL-36α<br />
100<br />
*<br />
*<br />
*<br />
15<br />
IL-36<br />
80<br />
60<br />
10<br />
40<br />
IL-1F6<br />
IL-1F9<br />
5<br />
20<br />
0<br />
0<br />
healthy<br />
pso<br />
healthy<br />
pso<br />
Muhr et al, Br J Dermatol, 2011
Tenocytes express IL-1F9<br />
Relative IL-1F9 mRNA levels (normalised to U6)<br />
30<br />
20<br />
10<br />
0<br />
NS<br />
IL-1alpha 1ng/ml<br />
IL-1alpha 10ng/ml<br />
IL-1alpha 100ng/ml<br />
Dermal fibrobl<strong>as</strong>ts Tendon fibrobl<strong>as</strong>ts
IL-1F9 protein expression in kertinocytes is<br />
induced by shear stress<br />
No stress<br />
No<br />
serum<br />
with<br />
serum<br />
Shear stress<br />
No<br />
serum<br />
with<br />
serum<br />
IL-1F9<br />
GAPDH
Incubation of full length IL-1F9 with Supernatant from<br />
stimulated neutrophils incre<strong>as</strong>es pro-inflammatory <strong>cytokine</strong><br />
production<br />
IL-6 (pg/ml)<br />
Full length F9 incubated with<br />
SN from activated neutrophils<br />
3000<br />
5min<br />
15min<br />
2000<br />
IL-8<br />
1000<br />
0<br />
ns<br />
NSN<br />
IL-1F9 + NSN<br />
IL-1F9 (100ng/ml)<br />
TNFa (10ng/ml)<br />
TNFa + F9<br />
TNFa + F9 + NSN<br />
• Isolated neutrophils activated with zymosan<br />
• SN incubated 15 min with full length F9<br />
• added to cells
IL-36<br />
Schulze-Tanzil et al.
Kin<strong>as</strong>e Inhibitors<br />
• Protein kin<strong>as</strong>es (= phosphotransfer<strong>as</strong>es) are<br />
components of signaling pathways<br />
• Several Janus kin<strong>as</strong>e inhibitors are being<br />
tested in clinical trials for autoimmune<br />
dise<strong>as</strong>es<br />
• Jak family consits of 4 members: Jak1, Jak2,<br />
Jak3 <strong>and</strong> Tyk2
Cytokine receptors signal directly by activating kin<strong>as</strong>es<br />
Cytokines that use type I <strong>and</strong> II <strong>cytokine</strong> receptors signal via the activation of<br />
receptor-<strong>as</strong>sociated Janus kin<strong>as</strong>es (Jaks)<br />
Approx. 60 which<br />
bind to type I/II R<br />
(IFNs, ILs, CSFs<br />
etc)<br />
Jaks are essential<br />
for signaling<br />
Quint<strong>as</strong>-Cardama, Nat Rev Drug Discovery 2011
Kontzi<strong>as</strong> et al, F1000<br />
Reports, 2012
Highly selective kin<strong>as</strong>e inhibitors have been disappointing in the treatment of<br />
autoimmune dise<strong>as</strong>es either due to toxicity <strong>and</strong>/or lack of efficacy
SOCS: Silencer of Cytokine Signaling<br />
Yoshimura et al. Nat Reviews Immunol 2007
Outlook<br />
• microRNA<br />
• Epigenetic
Hannover<br />
• Thom<strong>as</strong> Werfel<br />
• Philipp Muhr<br />
• Jana Zeitvogel<br />
• Julius Renne<br />
Leeds (Faculty of Biological Sciences)<br />
• Rosie Doble<br />
• Adenowola Al<strong>as</strong>e<br />
• Martin Stacey<br />
DFG grant SFB566/A6<br />
Leeds Foundation for<br />
Dermatological Research<br />
Leeds<br />
• Dennis McGonagle (Rheumatology)<br />
• Mark Goodfield (Dermatology)<br />
The Royal Society
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