Interleuchina-15 - Università degli Studi di Torino
Interleuchina-15 - Università degli Studi di Torino
Interleuchina-15 - Università degli Studi di Torino
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Università <strong>degli</strong> stu<strong>di</strong> <strong>di</strong> <strong>Torino</strong><br />
Anno Accademico 2006/2007<br />
Corso <strong>di</strong> Laurea Specialistica in Biotecnologie Molecolari<br />
Presentazione <strong>di</strong> Immunologia Molecolare<br />
<strong>Interleuchina</strong>-2<br />
Silvia Costa
<strong>Interleuchina</strong>-2<br />
• Scoperta nel 1975<br />
• Proteina <strong>di</strong> <strong>15</strong>kD<br />
• Classificazione:<br />
• STRUTTURALE: a catena corta<br />
• IN BASE ALLA SUBUNITA’ RECETTORIALE: IL-2Rγ<br />
• FUNZIONALE: risposta adattativa<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Struttura <strong>di</strong> IL-2<br />
1-Locus genico<br />
2-Struttura proteica<br />
con 4α-eliche<br />
tipica della<br />
famiglia delle<br />
citochine <strong>di</strong> tipo I<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
3-Sito <strong>di</strong> legame<br />
della proteina<br />
Struttura <strong>di</strong> IL-2<br />
Wang X. et al., Structure of the Quaternary Complex of Interleukin-2 with its α, β, and γc Receptors, Science, 310:1<strong>15</strong>9, 2005
Secrezione <strong>di</strong> IL-2 da parte <strong>di</strong>:<br />
• Cellule CD4 + T attivate<br />
• Cellule CD8 + T attivate<br />
• Cellule Thelper 1<br />
In minor quantità da:<br />
• Linfociti B<br />
• Cellule Dendritiche<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Sintesi <strong>di</strong> IL-2<br />
Otc-1<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Sintesi <strong>di</strong> IL-2<br />
Promotore prossimale <strong>di</strong> IL-2<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Regolazione <strong>di</strong> IL-2<br />
1-A livello trascrizionale:<br />
– Combinazione <strong>di</strong> più fattori <strong>di</strong> trascrizione<br />
– Struttura della cromatina<br />
– mRNA: AREs e CIS elements<br />
2-Inibitori naturali:<br />
– CTLA-4<br />
– Glucocorticoi<strong>di</strong><br />
– sIL-2Rα<br />
3-Stimolatore naturale:<br />
– Il-2<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Azione <strong>di</strong> IL-2<br />
Granucci F. et al., IL-2 me<strong>di</strong>ates adjuvant effect of dendritic cells, TRENDS in Immunology, 23:169, 200
Azione <strong>di</strong> IL-2<br />
Nella risposta innata:<br />
•Maturazione delle DC<br />
•Proliferazione delle cellule NK<br />
Nella risposta adattativa:<br />
•Mantenimento dell’omeostasi dei Linfociti T<br />
•Aiuto nella secrezione <strong>di</strong> Ab nei Linfociti B<br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004<br />
Reaeli Y. et al., Biochemical Mechanism of IL-2-Regulated Fas-Me<strong>di</strong>ated T Cell Apoptosis, Immunity, 8:6<strong>15</strong>, 1998
• HIV<br />
Importanza clinica <strong>di</strong> IL-2<br />
• Malattie autoimmuni: -scleroderma<br />
• Epatite B<br />
• Cancro<br />
-artriti reumatoi<strong>di</strong><br />
Gaffen S.L. et al., Owerview of interleukin-2 function, production and clinical applications, Cytokine, 28:109, 2004
Università <strong>degli</strong> stu<strong>di</strong> <strong>di</strong> <strong>Torino</strong><br />
Anno Accademico 2006/2007<br />
Corso <strong>di</strong> Laurea Specialistica in Biotecnologie Molecolari<br />
Presentazione <strong>di</strong> Immunologia Molecolare<br />
<strong>Interleuchina</strong>-<strong>15</strong><br />
Silvia Costa
<strong>Interleuchina</strong>-<strong>15</strong><br />
• Scoperta nel 1994<br />
• Altamente conservata<br />
• Proteina <strong>di</strong> <strong>15</strong>kD<br />
• Classificazione:<br />
• STRUTTURALE: a catena corta<br />
• IN BASE ALLA SUBUNITA’ RECETTORIALE: IL-2Rγ<br />
• FUNZIONALE: risposta innata<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
1-Sequenza genica<br />
Struttura <strong>di</strong> IL-<strong>15</strong><br />
1 2 3 4 4a 5 6 7 8<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Struttura <strong>di</strong> IL-<strong>15</strong><br />
2-Struttura proteica<br />
con 4α-eliche<br />
tipica della<br />
famiglia delle<br />
citochine <strong>di</strong> tipo I<br />
C<br />
A<br />
B<br />
N<br />
C<br />
D<br />
Lorenzen I. et al., The Structure of the Interleukin-<strong>15</strong>α<br />
Receptor and its Implication for Ligand Bin<strong>di</strong>ng, The<br />
Journal of Biological Chemistry, 281:6642, 2006<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Struttura <strong>di</strong> IL-<strong>15</strong><br />
3-Sito <strong>di</strong> legame della proteina<br />
IL-<strong>15</strong>Rα<br />
IL-<strong>15</strong><br />
Lorenzen I. et al., The Structure of the Interleukin-<strong>15</strong>α Receptor and its Implication for Ligand Bin<strong>di</strong>ng, The Journal of<br />
Biological Chemistry, 281:6642, 2006
Espressione <strong>di</strong> IL-<strong>15</strong><br />
1-A livello trascrizionale:<br />
L’mRNA è costitutivamente espresso in un<br />
gran numero <strong>di</strong> tipi cellulari e tessuti.<br />
2-A livello traduzionale:<br />
La proteina è espressa solo in<br />
• monociti/macrofagi<br />
• cellule epiteliali<br />
• DC<br />
• fibroblasti<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Sintesi <strong>di</strong> IL-<strong>15</strong><br />
Bulfone-Paus S. et al., The interleukin-<strong>15</strong>/interleukin-<strong>15</strong> receptor system as<br />
a model for juxtacrine and reverse signaling, BioEssays, 28:362, 2006<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Sintesi <strong>di</strong> IL-<strong>15</strong><br />
Nishimura H.et al., A novel autoregolatory mechanism for transcriptional activation of the IL-<strong>15</strong> gene by a nonsecretable<br />
isoform of IL-<strong>15</strong> generated by alternative splicing, FASEB J, 19:19, 2005
Regolazione dell’espressione <strong>di</strong> IL-<strong>15</strong><br />
• A livello trascrizionale:<br />
– NF-kB<br />
– IRF<br />
• A livello traduzionale:<br />
– AUGs multipli<br />
– Peptide segnale<br />
– Sito <strong>di</strong> clivaggio al C-terminale della<br />
proteina<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Azione <strong>di</strong> IL-<strong>15</strong><br />
Su cellule del<br />
Sistema Immunitario<br />
Bulfone-Paus S. et al., The interleukin-<br />
<strong>15</strong>/interleukin-<strong>15</strong> receptor system as a model for<br />
juxtacrine and reverse signaling, BioEssays,<br />
28:362, 2006<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Azione <strong>di</strong> IL-<strong>15</strong><br />
Su cellule NON del<br />
Sistema Immunitario<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor<br />
biology: A guided tour through an expan<strong>di</strong>ng<br />
universe, Cytokine & Growth Factor Reviews,<br />
17:259, 2006
Importanza clinica <strong>di</strong> IL-<strong>15</strong><br />
• Artriti reumatoi<strong>di</strong><br />
• Malattie infiammatorie dell’intestino<br />
• Lupus erimatosi sistemica<br />
• Malattie autoimmuni: -Diabete Mellito<br />
-Psoriasi<br />
• Ipertensione ed arteriosclerosi<br />
• Malattie muscolari<br />
• Crescita tumorale<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Confronto tra IL-2 e IL-<strong>15</strong><br />
• SIMILITUDINI:<br />
– Appartengono alla famiglia <strong>di</strong> citochine <strong>di</strong> tipo I<br />
– Hanno una struttura con 4α-eliche<br />
– Hanno i recettori IL-2Rβ e IL-2Rγ/γc in comune<br />
– Hanno un’azione simile su cellule dello stesso tipo<br />
• DIFFERENZE:<br />
– IL-2 modula la risposta adattativa,<br />
IL-<strong>15</strong> ha uno spettro d’azione più vasto<br />
– IL-2 viene regolata maggiormente a livello trascrizionale,<br />
IL-<strong>15</strong> a livello post-trascrizionale<br />
Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an expan<strong>di</strong>ng universe, Cytokine & Growth<br />
Factor Reviews, 17:259, 2006
Bibliografia<br />
• Gaffen S.L.. et al., Owerview of interleukin-2 function, production and clinical<br />
applications, Cytokine, 28:109, 2004<br />
• Wang X. et al., Structure of the Quaternary Complex of Interleukin-2 with its α, β,<br />
and γc Receptors, Science, 310:1<strong>15</strong>9, 2005<br />
• Granucci F. et al., IL-2 me<strong>di</strong>ates adjuvant effect of dendritic cells, TRENDS in<br />
Immunology, 23:169, 2002<br />
• Reaeli Y. et al., Biochemical Mechanism of IL-2-Regulated Fas-Me<strong>di</strong>ated T Cell<br />
Apoptosis, Immunity, 8:6<strong>15</strong>, 1998<br />
• Antony P.A. et al., CD4+CD25+ T Regularory Cells, Immunotherapy of Cancer,<br />
and Interleukin-2, J. Immunother, 28:120, 2005<br />
• Budagian V. et al., IL-<strong>15</strong>/IL-<strong>15</strong> receptor biology: A guided tour through an<br />
expan<strong>di</strong>ng universe, Cytokine & Growth Factor Reviews, 17:259, 2006<br />
• Lorenzen I. et al., The Structure of the Interleukin-<strong>15</strong>α Receptor and its Implication<br />
for Ligand Bin<strong>di</strong>ng, The Journal of Biological Chemistry, 281:6642, 2006<br />
• Bulfone-Paus S. et al., The interleukin-<strong>15</strong>/interleukin-<strong>15</strong> receptor system as a<br />
model for juxtacrine and reverse signaling, BioEssays, 28:362, 2006<br />
• Nishimura H.et al., A novel autoregolatory mechanism for transcriptional activation<br />
of the IL-<strong>15</strong> gene by a nonsecretable isoform of IL-<strong>15</strong> generated by alternative<br />
splicing, FASEB J, 19:19, 2005
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