Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease.
OBJECTIVE
T-helper (Th)1 cells play a central role in the pathogenesis of tissue damage in Crohn's disease (CD). Interleukin (IL)-12/STAT4 signaling promotes Th1 cell commitment in CD, but other cytokines are needed to maintain activated Th1 cells in the mucosa. In this study, we examined the expression and role of IL-21, a T-cell-derived cytokine of the IL-2 family; in tissues and cells isolated from patients with inflammatory bowel disease.


METHODS
IL-21 was examined by Western blotting in whole mucosa and lamina propria mononuclear cells (LPMCs) from patients with CD, ulcerative colitis (UC), and controls. We also examined the effects of exogenous IL-12 on IL-21 production, as well as the effects of blocking IL-21 with an IL-21-receptor Ig fusion protein. Interferon (IFN)-gamma was measured in the culture supernatants by enzyme-linked immunosorbent assay, and phosphorylated STAT4 and T-bet were examined by Western blotting.


RESULTS
IL-21 was detected in all samples, but its expression was higher at the site of disease in CD in comparison with UC and controls. Enhanced IL-21 was seen in both ileal and colonic CD and in fibrostenosing and nonfibrostenosing disease. IL-12 enhanced IL-21 in normal lamina propria lymphocytes through an IFN-gamma-independent mechanism, and blocking IL-12 in CD LPMCs decreased anti-CD3-stimulated IL-21 expression. Neutralization of IL-21 in CD LPMC cultures decreased phosphorylated STAT4 and T-bet expression, thereby inhibiting IFN-gamma production.


CONCLUSIONS
Our data suggest that IL-21 contributes to the ongoing Th1 mucosal response in CD.
Monteleone
Giovanni
G
Dipartimento di Medicina Interna e Centro di Eccellenza per lo studio delle malattie complesse e multifattoriali, Università Tor Vergata, Rome, Italy. Gi.Monteleone@Med.uniroma2.it
Monteleone
Ivan
I
Fina
Daniele
D
Vavassori
Piero
P
Del Vecchio Blanco
Giovanna
G
Caruso
Roberta
R
Tersigni
Roberto
R
Alessandroni
Luciano
L
Biancone
Livia
L
Naccari
Gian Carlo
GC
MacDonald
Thomas T
TT
Pallone
Francesco
F
D015153:Blotting, Western; D016022:Case-Control Studies; D002478:Cells, Cultured; D003093:Colitis, Ulcerative / Q000378:metabolism / Q000473:pathology; D003424:Crohn Disease / Q000378:metabolism* / Q000473:pathology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D007378:Interleukins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction; D018417:Th1 Cells / Q000378:metabolism*; D000098546:Interleukin-21
D007378:Interleukins; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma; D000098546:Interleukin-21