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The Role of IL-13 and the IL-13Rα2 Pathway in the Pathogenesis of Experimental and Human Ulcerative Colitis
The Role of IL-13 and the IL-13Rα2 Pathway in the Pathogenesis of Experimental and Human Ulcerative Colitis
Ivan J. Fuss
Mucosal Immunity SectionLaboratory of Host DefensesNIAID, National Institutes of Health
NKT Cells and IL-13 in Experimental Colitis
Fuss et al J Clin Invest 2004Heller et al Immunity 2002
• IL-13 caused a dose-dependent decrease in electrical resistance of HT-29 epithelial cell monolayers.
• This was associated with an increase in the cellular apoptotic rate.
• Addition of IL-13 in vitro led to an increased expression of the pore-forming tight junction protein claudin-2.
IL-13 Can Effect Epithelial Cell Barrier Function
Heller et al Gastroenterology 2005
Heller et al Gastroenterology 2005
Gut Lumen
Glycolipid antigen ?
Epithelium
APCNKT
NKT
NKT
CD1Glycolipid ?
IL-13
CytokineTranscription
TGF-βTranscription
IL-13
Type IIL-4 Receptor
JAK 3JAK-1 B
OX1
IL-4
STAT 6
IL-4Rα
BOX1
P
IRS-1/2
Type IIIL-4 Receptor
Tyk 2JAK-1BOX1
IL-4
STAT 6
IL-4Rα
BOX1
P
IRS-1/2
IL-13Rα1
STAT 6
Tyk 2JAK-1BOX1
IL-4
STAT 6
IL-4Rα
BOX1
P
IRS-1/2
IL-13Rα1
IL-13
IL-13 Receptor IL-13 Receptor
IL-13Rα2
STAT 6
STAT 6
AP-1
AP-1
?
Fichtner-Feigl et al Nat Med 2006
Specificity of Action
% In
itial
Bod
y W
eigh
t Day
0
105
100
95
90
850 1 2 3 4
Days
Ethanol
Oxazolone
Oxazolone + IL-13 PE
Treatment with an IL-13 Pseudomonas Exotoxin canAmeliorate Experimental Ulcerative Colitis (Oxazolone)
CD3/CD28
CD3/CD28 + IL-13PE
0
100
200
300
400
500
600
IL-1
3 Se
cret
ion
(pg/
ml)
Treatment of Oxazolone Colitis with a IL-13 PEleads to Decreased IL-13 Secreting Cells
Crohn’s Disease
103102101100
103
102
101
100
Ulcerative Colitis
104
104
103102101100
103
102
101
100
104
104
CD161 CD161
IL-1
3Rα2
IL-1
3Rα2
Increased IL-13Rα2 Bearing NKT Cellsin PBMC of Ulcerative Colitis Patients
CD2/CD28
CD2/CD28 + IL-13PE
0
100
200
300
400
500
600
IL-1
3 Se
cret
ion
(pg/
ml)
IL-13 Secretion From an Ulcerative Colitis Patient LPMC After Treatment with IL-13 Pseudomonas Exotoxin
CD2/CD28
CD2/CD28 + IL-13PE
0
100
200
300
400
500
600
IL-1
3 Se
cret
ion
(pg/
ml)
IL-13 Secretion From an Crohn’s Disease Patient LPMC After Treatment with IL-13 Pseudomonas Exotoxin
Gut Lumen
Glycolipid antigen ?
Epithelium
APCNKT
NKT
NKT
CD1Glycolipid ?
IL-13
IL-13Rα2
Summary
Treatment of experimental ulcerative colitis with anIL-13 PE can ameliorate disease.
LPMC NKT cells from ulcerative colitis patients demonstrate an increased expression of IL-13Rα2.
Treatment of ulcerative colitis NKT cells with an IL-13 PE leads to decreased IL-13 secretion.
Therapeutic modalities that target the IL−13Rα2 pathway may be a new avenue of treatment for ulcerative colitis.
Acknowledgements
• Frank Heller• Zhiqiong Yang• Stefan Fichtner-Feigl• Bharat Joshi• Raj Puri• Peter Mannon• Warren Strober