Loss of TGF-β signaling contributes to autoimmune pancreatitis

Hahm, Ki Baik; Im, Young Hyuck; Lee, Cecile; Parks, W. Tony; Bang, Yung Jue; Green, Jeffrey E.; Kim, Seong‐Jin

doi:10.1172/jci8337

Cited by 70 publications

(57 citation statements)

References 39 publications

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“…More recently, selective pancreatic expression using the trefoil peptide promoter increased susceptibility to cerulean-induced pancreatitis (30). Previous studies expressing T␤RII⌬k in mesenchymal cells, whose growth or differentiation is likely to be promoted rather than inhibited by TGF␤ stimulation, probably better reflect the present study.…”

Section: Fibroblast-specific Perturbation Of Tgf␤ Signalingsupporting

confidence: 54%

Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor β (TGFβ) Receptor Leads to Paradoxical Activation of TGFβ Signaling Pathways with Fibrosis in Transgenic Mice

Denton

Zheng

Evans

et al. 2003

Journal of Biological Chemistry

130

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To better understand the role of disrupted transforming growth factor ␤ (TGF␤) signaling in fibrosis, we have selectively expressed a kinase-deficient human type II TGF␤ receptor (T␤RII⌬k) in fibroblasts of transgenic mice, using a lineage-specific expression cassette subcloned from the pro-␣2(I) collagen gene. Surprisingly, despite previous studies that characterized T␤RII⌬k as a dominant negative inhibitor of TGF␤ signaling, adult mice expressing this construct demonstrated TGF␤ overactivity and developed dermal and pulmonary fibrosis. Compared with wild type cells, transgenic fibroblasts proliferated more rapidly, produced more extracellular matrix, and showed increased expression of key markers of TGF␤ activation, including plasminogen activator inhibitor-1, connective tissue growth factor, Smad3, Smad4, and Smad7. Smad2/3 phosphorylation was increased in transgenic fibroblasts. Overall, the gene expression profile of explanted transgenic fibroblasts using cDNA microarrays was very similar to that of littermate wild type cells treated with recombinant TGF␤1. Despite basal up-regulation of TGF␤ signaling pathways, transgenic fibroblasts were relatively refractory to further stimulation with TGF␤1. Thus, responsiveness of endogenous genes to TGF␤ was reduced, and TGF␤-regulated promoter-reporter constructs transiently transfected into transgenic fibroblasts showed little activation by recombinant TGF␤1. Responsiveness was partially restored by overexpression of wild type type II TGF␤ receptors. Activation of MAPK pathways by recombinant TGF␤1 appeared to be less perturbed than Smad-dependent signaling. Our results show that expression of T␤RII⌬k selectively in fibroblasts leads to paradoxical ligand-dependent activation of downstream signaling pathways and causes skin and lung fibrosis. As well as confirming the potential for nonsignaling receptors to regulate TGF␤ activity, these findings support a direct role for perturbed TGF␤ signaling in fibrosis and provide a novel genetically determined animal model of fibrotic disease.Transforming growth factor ␤ (TGF␤) 1 isoforms ␤1-␤3 are important regulators of embryonic and postnatal cell differentiation and proliferation. They are also potent profibrotic factors in vitro. Transgenic and gene-targeted mutant mice have proven valuable for investigating the important roles of the TGF␤ family in growth and development. For example, mice lacking TGF␤1 show substantial embryonic lethality, and those that are born develop a fatal disseminated inflammatory illness within the first postnatal month. Conversely, mice lacking TGF␤2 all die neonatally with defective epithelial-mesenchymal interaction, whereas mice lacking TGF␤3 show a perinatal lethal phenotype with cleft palate (1). These different knock-out phenotypes suggest somewhat distinct biological functions in vivo, although all three TGF␤ isoforms signal though the same specific receptor complex, so differential effects are likely to reflect patterns of ligand expression or the influence of accessory receptors at the...

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Section: Fibroblast-specific Perturbation Of Tgf␤ Signalingsupporting

confidence: 54%

Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor β (TGFβ) Receptor Leads to Paradoxical Activation of TGFβ Signaling Pathways with Fibrosis in Transgenic Mice

Denton

Zheng

Evans

et al. 2003

Journal of Biological Chemistry

130

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“…Loss of TGF-␤ signaling in TGF-␤ dominant negative mutant mice might contribute to AIP (Hahm et al, 2000). TGF-␤ gene expression in our mouse model was not different compared with control mice (data not shown).…”

Section: Uchida Et Almentioning

confidence: 64%

Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Uchida

Okazaki

Nishi

et al. 2002

Laboratory Investigation

109

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SUMMARY:We previously reported that autoantibodies against carbonic anhydrase II and lactoferrin are frequently identified in patients with autoimmune-related pancreatitis. To clarify the role of carbonic anhydrase II and lactoferrin, we created animal models of autoimmune pancreatitis by immunizing neonatally thymectomized mice with carbonic anhydrase II and lactoferrin and also by transferring immunized spleen cells to nude mice. Neonatally thymectomized BALB/c mice were immunized with carbonic anhydrase II or lactoferrin followed by three booster injections

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“…TGF-␤ is a potent inhibitor of MMP gene expression in mesenchymal cells (50 -52). Matrix degrading activity is constitutively elevated in mice with genetic disruption of TGF-␤ signaling, highlighting the physiological significance of negative MMP regulation by TGF-␤ (53). Previous studies investigating the mechanistic basis of MMP-1 inhibition demonstrated that IL-1 receptor expression was reduced by TGF-␤ treatment in a variety of cell types (25,54).…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor-β Repression of Matrix Metalloproteinase-1 in Dermal Fibroblasts Involves Smad3

Yuan¹,

Varga²

2001

Journal of Biological Chemistry

246

156

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Loss of TGF-β signaling contributes to autoimmune pancreatitis

Cited by 70 publications

References 39 publications

Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor β (TGFβ) Receptor Leads to Paradoxical Activation of TGFβ Signaling Pathways with Fibrosis in Transgenic Mice

Fibroblast-specific Expression of a Kinase-deficient Type II Transforming Growth Factor β (TGFβ) Receptor Leads to Paradoxical Activation of TGFβ Signaling Pathways with Fibrosis in Transgenic Mice

Experimental Immune-Mediated Pancreatitis in Neonatally Thymectomized Mice Immunized with Carbonic Anhydrase II and Lactoferrin

Transforming Growth Factor-β Repression of Matrix Metalloproteinase-1 in Dermal Fibroblasts Involves Smad3

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