TY - JOUR

T1 - IL-33 promotes GATA-3 polarization of gut-derived T cells in experimental and ulcerative colitis

AU - Seidelin, Jakob Benedict

AU - Coskun, Mehmet

AU - Kvist, Peter Helding

AU - Holm, Thomas Lindebo

AU - Holgersen, Kristine

AU - Nielsen, Ole Haagen

PY - 2015/2

Y1 - 2015/2

N2 - BACKGROUND: In the respiratory mucosa, interleukin (IL)-33, has been shown to enhance T helper 2 (TH2)-type responses through the master regulatory gene GATA-3. IL-33 is upregulated in ulcerative colitis (UC), and the aim was to assess if IL-33 holds a similar key position in the shaping of the immune response in experimental colitis (piroxicam-accelerated colitis (PAC) in IL-10 -/- mice, dextran sodium sulfate (DSS) model) and UC.METHODS: Colonic IL-33 expression was determined in UC (8 active UC, 8 quiescent UC, and 7 controls) and experimental colitis. Mesenteric lymph node (MesLN) T cells were isolated from PAC IL-10 -/- mice and stimulated with IL-33.RESULTS: The colonic IL-33 expression was significantly upregulated all forms of colitis (P < 0.01) and correlated with disease severity score and inflammation (P < 0.001), and with GATA-3 expression levels (P < 0.01); no correlation with the TH1-specific T-bet expression was observed. MesLN T cells stimulated with IL-33 had increased GATA-3 expression, and showed an IL-33 dose-dependent increase in secreted TH2-type cytokines, whereas this effect was abolished by blocking IL-33 signaling. The non-TH2-type cytokine IL-17 was upregulated by IL-33 but in a T cell receptor dependent manner, as opposed to TH2-type cytokines, which required only IL-33 stimulation.CONCLUSIONS: The study demonstrates that intestinal IL-33 is capable of inducing GATA-3 in mucosal T cells, and suggests that IL-33 is a key mediator of pathological TH2 and non-TH2-type responses in intestinal inflammation. Blocking IL-33 signaling could be a feasible option in the treatment of UC.

AB - BACKGROUND: In the respiratory mucosa, interleukin (IL)-33, has been shown to enhance T helper 2 (TH2)-type responses through the master regulatory gene GATA-3. IL-33 is upregulated in ulcerative colitis (UC), and the aim was to assess if IL-33 holds a similar key position in the shaping of the immune response in experimental colitis (piroxicam-accelerated colitis (PAC) in IL-10 -/- mice, dextran sodium sulfate (DSS) model) and UC.METHODS: Colonic IL-33 expression was determined in UC (8 active UC, 8 quiescent UC, and 7 controls) and experimental colitis. Mesenteric lymph node (MesLN) T cells were isolated from PAC IL-10 -/- mice and stimulated with IL-33.RESULTS: The colonic IL-33 expression was significantly upregulated all forms of colitis (P < 0.01) and correlated with disease severity score and inflammation (P < 0.001), and with GATA-3 expression levels (P < 0.01); no correlation with the TH1-specific T-bet expression was observed. MesLN T cells stimulated with IL-33 had increased GATA-3 expression, and showed an IL-33 dose-dependent increase in secreted TH2-type cytokines, whereas this effect was abolished by blocking IL-33 signaling. The non-TH2-type cytokine IL-17 was upregulated by IL-33 but in a T cell receptor dependent manner, as opposed to TH2-type cytokines, which required only IL-33 stimulation.CONCLUSIONS: The study demonstrates that intestinal IL-33 is capable of inducing GATA-3 in mucosal T cells, and suggests that IL-33 is a key mediator of pathological TH2 and non-TH2-type responses in intestinal inflammation. Blocking IL-33 signaling could be a feasible option in the treatment of UC.

KW - Faculty of Health and Medical Sciences

KW - Experimental colitis

KW - GATA-3

KW - Interleukin-33

KW - T-bet

KW - Ulcerative colitis

U2 - 10.1007/s00535-014-0982-7

DO - 10.1007/s00535-014-0982-7

M3 - Journal article

C2 - 25112700

VL - 50

SP - 180

EP - 190

JO - Journal of Gastroenterology

JF - Journal of Gastroenterology

SN - 0944-1174

IS - 2

ER -