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Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis.

Miller KJ, Raulefs S, Kong B, Steiger K, Regel I, Gewies A, Kleeff J, Michalski CW - PLoS ONE (2015)

Bottom Line: Type I interferon constitutes an essential component of the combinational therapy against viral disease.Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage.Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Technische Universität München, Munich, Germany.

ABSTRACT
Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

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Proinflammatory cytokine expression in WT and Ifnardel mice.(A-B) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (A) and the anti-inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (B) from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (C-D) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (C) and the anti- inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (D) from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test).
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pone.0143735.g005: Proinflammatory cytokine expression in WT and Ifnardel mice.(A-B) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (A) and the anti-inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (B) from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (C-D) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (C) and the anti- inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (D) from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test).

Mentions: To investigate whether the aberrant macrophage infiltration in Ifnardel mice was based on changes in cytokine expression we analyzed the cytokine expression levels of either untreated or treated WT and Ifnardel mice. We chose a set of proinflammatory cytokines (Ifnγ, Tnfα, IL-6, LBP, G-Csf, Ifnα, IL-1α, IL-1β) and anti-inflammatory cytokines (IL-10, IL-13, Tgfβ, Csf) important for the activation of macrophages [33] and performed qRT PCR analysis (Fig 5). Gene expression at mRNA level of caerulein- treated mice revealed a strong upregulation of the proinflammatory cytokines Tnfα, IL-6 and IL-1β (Fig 5A) and only a mild increase of the mRNA of the anti-inflammatory cytokines IL-10, Tgfβ1 and Csf (Fig 5B) in both genotypes. Interestingly, even untreated Ifnardel mice exhibited extremely high mRNA levels of Tnfα, IL-6, IL-1α, IL-1β and G-Csf (Fig 5C) and an upregulation of IL-10 and Csf (Fig 5D).


Loss of Ifnar1 in Pancreatic Acinar Cells Ameliorates the Disease Course of Acute Pancreatitis.

Miller KJ, Raulefs S, Kong B, Steiger K, Regel I, Gewies A, Kleeff J, Michalski CW - PLoS ONE (2015)

Proinflammatory cytokine expression in WT and Ifnardel mice.(A-B) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (A) and the anti-inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (B) from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (C-D) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (C) and the anti- inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (D) from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test).
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pone.0143735.g005: Proinflammatory cytokine expression in WT and Ifnardel mice.(A-B) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (A) and the anti-inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (B) from whole pancreatic tissue of WT and Ifnardel mice harvested 4 hours following caerulein-induced injury (n = 3 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib). (C-D) qRT PCR analysis of mRNA levels of the proinflammatory cytokines Ifnγ, Tnfα, IL-6, Lbp, G-Csf, Ifnα, IL-1α and IL-1β (C) and the anti- inflammatory cytokines IL-10, IL-13, Tgfβ1–3 and Csf (D) from whole pancreatic tissue of untreated WT and Ifnardel mice (n = 7 per group. Bars indicate mean +/- SD. Normalized on the mRNA of the housekeeping gene Ppib. *P<0.05, unpaired Student´s t-test).
Mentions: To investigate whether the aberrant macrophage infiltration in Ifnardel mice was based on changes in cytokine expression we analyzed the cytokine expression levels of either untreated or treated WT and Ifnardel mice. We chose a set of proinflammatory cytokines (Ifnγ, Tnfα, IL-6, LBP, G-Csf, Ifnα, IL-1α, IL-1β) and anti-inflammatory cytokines (IL-10, IL-13, Tgfβ, Csf) important for the activation of macrophages [33] and performed qRT PCR analysis (Fig 5). Gene expression at mRNA level of caerulein- treated mice revealed a strong upregulation of the proinflammatory cytokines Tnfα, IL-6 and IL-1β (Fig 5A) and only a mild increase of the mRNA of the anti-inflammatory cytokines IL-10, Tgfβ1 and Csf (Fig 5B) in both genotypes. Interestingly, even untreated Ifnardel mice exhibited extremely high mRNA levels of Tnfα, IL-6, IL-1α, IL-1β and G-Csf (Fig 5C) and an upregulation of IL-10 and Csf (Fig 5D).

Bottom Line: Type I interferon constitutes an essential component of the combinational therapy against viral disease.Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage.Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

View Article: PubMed Central - PubMed

Affiliation: Department of Surgery, Technische Universität München, Munich, Germany.

ABSTRACT
Type I interferon constitutes an essential component of the combinational therapy against viral disease. Acute pancreatitis is one side effect of type I interferon-based therapy, implying that activation of type I interferon signaling affects the homeostasis and integrity of pancreatic acinar cells. Here, we investigated the role of type I interferon signaling in pancreatic acinar cells using a caerulein-induced murine model of acute pancreatitis. Pancreas-specific ablation of interferon (alpha and beta) receptor 1 (Ifnar1) partially protected animals from caerulein-induced pancreatitis, as demonstrated by reduced tissue damage. Profiling of infiltrating immune cells revealed that this dampened tissue damage response correlated with the number of macrophages in the pancreas. Pharmacologic depletion of macrophages reversed the protective effect of Ifnar1 deficiency. Furthermore, expression of chemokine (C-C motif) ligand 2 (Ccl2), a potent factor for macrophage recruitment, was significantly increased in the Ifnar1-deficient pancreas. Thus, type I interferon signaling in pancreatic acinar cells controls pancreatic homeostasis by affecting the macrophage-mediated inflammatory response in the pancreas.

Show MeSH
Related in: MedlinePlus