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. 2012 Jun;180(6):2330-9.
doi: 10.1016/j.ajpath.2012.03.009. Epub 2012 Apr 24.

The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice

Romy Ouziel  1 , Thierry Gustot, Christophe Moreno, Marianna Arvanitakis, Delphine Degré, Eric Trépo, Eric Quertinmont, Vincent Vercruysse, Pieter Demetter, Olivier Le Moine, Andrew N J McKenzie, Myriam Delhaye, Jacques Devière, Arnaud Lemmers
Affiliations

The ST2 pathway is involved in acute pancreatitis: a translational study in humans and mice

Romy Ouziel et al. Am J Pathol. 2012 Jun.

Abstract

Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathways are not clearly elucidated. Activation of interleukin 1β (IL-1β) and immunomodulation via MyD88, the first signaling molecule in the ST2 pathway, seem to be involved. Because IL-33, the ST2 ligand, is an IL-1 family member and acts as an alarmin, we explored the ST2 pathway in human and mouse AP. Soluble ST2 was assayed by enzyme-linked immunosorbent assay (ELISA) in plasma of 44 patients admitted for AP. The levels of soluble ST2 increased early during AP and correlated with parameters of severity. Under two different experimental models of AP (ie, choline-deficient-ethionine-supplemented diet and cerulein injections), ST2-deficient mice (Il1rl1(-/-)) presented with more severe disease than wild-type mice, with increased activation of mast cells. In vitro, Il1rl1(-/-) bone-marrow-derived mast cells exhibited exacerbated degranulation, compared with the wild type. Flow cytometry identified mast cells as the main peritoneal population expressing ST2. Using immunohistochemistry and ELISA, we showed constitutive expression of IL-33 in murine pancreas and its release during experimental AP. Correlated with AP severity, increased soluble ST2 levels evoke involvement of the ST2 pathway in human AP. Furthermore, our experimental data suggest a protective role for ST2 during AP, highlighting the potential regulatory role of mast cells and the possibility of the ST2 pathway as a new therapeutic target in AP.

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Figures

Figure 1
Figure 1
sST2 levels in humans. Plasma sST2 levels measured in patients (n = 44) admitted within 24 hours of onset of AP symptoms, compared with healthy subjects (HS) (n = 16). Blood sample puncture was performed at days 0, 1, 2, 7, and 30. †P < 0.01 versus HS; *P < 0.05; **P < 0.01 AP day 30 versus other AP blood sample times.
Figure 2
Figure 2
CDE diet model in WT mice and ST2-deficient Il1rl1−/− mice (ST2−/−). Serum amylase (A) and lipase (B) levels were measured in mice exposed to the CDE diet for 0, 48, and 72 hours. Data are presented as means ± SEM of pooled data of 10 (baseline) to 24 (CDE group) mice per group from seven independent experiments. C: H&E staining for histological assessment of the pancreas after 72 hours of CDE diet in WT and Il1rl1−/− mice. Original magnification, ×200. D: Semiquantification of histological severity of pancreatitis in WT (n = 24) and Il1rl1−/− (n = 15) mice fed a CDE diet for 72 hours. E, edema; I, inflammation; N, necrosis; V, vacuolization. Data are presented as pooled scores from five independent experiments. E: IL-6 levels assessed by ELISA in serum of WT and Il1rl1−/− mice during CDE diet-induced AP. Data are presented as means ± SEM of pooled data of 15 (baseline) to 33 (CDE group) mice per group from nine independent experiments. *P < 0.05 versus baseline; †P < 0.01 WT versus Il1rl1−/− at 72 hours (A and B). *P < 0.05 WT versus Il1rl1−/−; **P < 0.01 WT versus Il1rl1−/− (D). †P = 0.001 WT versus Il1rl1−/− at 72 hours (E).
Figure 3
Figure 3
Cerulein model. Serum amylase (A) and lipase (B) levels measured in WT (and Il1rl1−/− mice exposed to 10 hourly cerulein or vehicle (Veh) injections. Data are presented as means ± SEM of pooled data of 4 (vehicle) to 30 (cerulein) mice per group from three independent experiments. *P < 0.01 versus vehicle. †P < 0.01 WT versus Il1rl1−/− after cerulein. C: H&E staining for histological assessment of the pancreas after cerulein in WT and Il1rl1−/− mice. Original magnification, ×200. D: Semiquantification of histological severity of pancreatitis in WT (n = 30) and Il1rl1−/− (n = 30) mice exposed to cerulein. E, edema; I, inflammation; N, necrosis. Data are presented as means ± SEM of pooled values from three independent experiments. *P < 0.01 WT versus Il1rl1−/−.
Figure 4
Figure 4
ST2 and IL-33 mRNA expression. A: HPRT (housekeeping gene), ST2, and IL-33 mRNA constitutive pancreatic expression was detected by classical RT-PCR on freshly isolated WT and Il1rl1−/− pancreas. Each analysis was performed in duplicate. B: Flow cytometry analysis of peritoneal cells isolated from mice focusing on c-kit+ FceRI+ cells (mast cells) (left panel) shows their ST2 expression in WT mice but not in the negative control Il1rl1−/− mice (right panel). FITC, fluorescein isothiocyanate; PE, phycoerythrin; APC, allophycocyanin.
Figure 5
Figure 5
Mast cell involvement in pancreatitis. A: Toluidine blue staining of WT mouse pancreas exposed to 72 hours of CDE diet indicates mast cells (arrows) in interlobular septa (left) and peripancreatic tissue (right). Original magnification, ×200. B: Tryptase concentration in sera of WT and Il1rl1−/− mice at baseline and after 72 hours of CDE diet. Data are presented as mean ± SEM of pooled data of 5 (baseline) to 12 (72 hours CDE diet) mice per group from three independent experiments. C: BMMCs expressing c-kit and FceRI (left) from WT and Il1rl1−/− mice were isolated (right). The percentage of cells is indicated in each quadrant (left). FITC, fluorescein isothiocyanate; PE, phycoerythrin; APC, allophycocyanin. D: Tryptase activity was measured in the supernatants of BMMCs. Degranulation was either stimulated (S) by calcium ionophore (10 nmol/L) or inhibited (I) by protamine (100 nmol/L). Data are presented as mean ± SEM of pooled data from four independent experiments. *P < 0.01 versus baseline; †P < 0.05 WT versus Il1rl1−/− (B). *P < 0.05 WT versus Il1rl1−/− BMMCs (D).
Figure 6
Figure 6
Pancreatic and plasma expression of IL-33. A: Immunohistochemical expression of IL-33 in the pancreas of control WT mice. IL-33 (left) and control isotype (right) immunostaining reveals acinar cell IL-33 expression. Original magnification, ×200. B: ELISA quantification of serum IL-33 levels after the indicated time of CDE diet in mice. C and D: Inflammatory activity of BMMCs isolated from WT and Il1rl1−/− mice was evaluated by ELISA quantification of IL-6 (C) and IL-13 (D) production in supernatants of BMMCs nonstimulated (NS) or stimulated by LPS or rIL-33. Data are presented as mean ± SEM of pooled values of seven independent experiments, each comprising three to nine mice per group (B), or of duplicate data representative of three independent experiments (C and D). **P < 0.001 versus control group. †P < 0.05 48 hours versus 72 hours of CDE diet.
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