IL-15 positively regulates IL-21 production in celiac disease mucosa.
Celiac disease (CD)-associated inflammation is characterized by high interleukin- 21 (IL-21), but the mechanisms that control IL-21 production are not fully understood. Here we analyzed IL-21 cell sources and examined how IL-21 production is regulated in CD. Intraepithelial lymphocytes (IELs) and lamina propria lymphocytes (LPLs), isolated from CD patients and non-CD controls, were analyzed for cell markers, cytokines, and transcription factors by flow cytometry. IL-21 was highly produced by CD4+ and CD4+/CD8+ IELs and LPLs in active CD. IL-21-producing cells coexpressed interferon-γ (IFN-γ) and to a lesser extent T helper type 17 (Th17) cytokines. Treatment of control LPLs with IL-15, a cytokine overproduced in CD, activated Akt and STAT3 (signal transducer and activator of transcription 3), thus enhancing IL-21 synthesis. Active CD biopsies contained elevated levels of Akt, and blockade of IL-15 in those samples reduced IL-21. Similarly, neutralization of IL-15 in biopsies of inactive CD patients inhibited peptic-tryptic digest of gliadin-induced IL-21 expression. These findings indicate that in CD, IL-15 positively regulates IL-21 production.
Department of Internal Medicine, University Tor Vergata of Rome, Rome, Italy.
M
M
Sarra
M L
ML
Cupi
I
I
Monteleone
E
E
Franzè
G
G
Ronchetti
A
A
Di Sabatino
P
P
Gentileschi
L
L
Franceschilli
P
P
Sileri
G
G
Sica
G
G
Del Vecchio Blanco
M
M
Cretella
O A
OA
Paoluzi
G R
GR
Corazza
F
F
Pallone
G
G
Monteleone
D002446:Celiac Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D007378:Interleukins / Q000096:biosynthesis* / Q000235:genetics; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D019409:Interleukin-15; D007378:Interleukins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054380:Receptors, CXCR5; D007371:Interferon-gamma; D051057:Proto-Oncogene Proteins c-akt; D000098546:Interleukin-21