Tumor Necrosis Factor-α Induces Transforming Growth Factor-β<sub>1</sub>Expression in Lung Fibroblasts Through the Extracellular Signal–Regulated Kinase Pathway

Sullivan, Deborah E.; Ferris, MaryBeth; Pociask, Derek; Brody, Arnold R.

doi:10.1165/rcmb.2004-0288oc

Cited by 154 publications

(139 citation statements)

References 47 publications

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“…In contrast, we found that pemphigoid fibroblasts showed a late contraction response to TNF␣ whereas normal conjunctival fibroblasts did not. This could perhaps be due to TNF␣ stimulating expression of TGF␤ 31 by the pemphigoid fibroblasts. This requires further investigation.…”

Section: Discussionmentioning

confidence: 99%

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Saw

Schmidt

Offiah

et al. 2011

The American Journal of Pathology

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Ocular mucous membrane pemphigoid is an immunobullous disease in which excessive conjunctival fibrosis causes blindness, and the pathogenesis of scarring is incompletely understood. To establish whether profibrotic fibroblasts with an altered phenotype exist in ocular mucous membrane pemphigoid, we compared the functional characteristics of pemphigoid conjunctival fibroblasts to normal conjunctival fibroblasts with respect to cell division; migration; collagen contraction; matrix metalloproteinase, secretion of collagen and chemokines; and myofibroblast differentiation. We found that pemphigoid fibroblasts showed increased cell division (P ‫؍‬ 0.01), increased migration in serum-free medium (72 ؎ 18 migrated cells versus 33 ؎ 11, P ‫؍‬ 0.04), increased collagen contraction in the presence of 10 ng/ml tumor necrosis factor-␣, increased collagen type I secretion (P ‫؍‬ 0.03), increased secretion of matrix metalloproteinase-3 (P ‫؍‬ 0.03), and increased secretion of eotaxin in response to interleukin-13 (P ‫؍‬ 0.04). Differences between pemphigoid and normal conjunctival fibroblasts with respect to collagen contraction and MMP secretion in the presence of interleukin-13 were also observed. Together, these findings indicate that pemphigoid conjunctival fibroblasts have a profibrotic phenotype that is maintained in vitro. No differences between pemphigoid fibroblasts obtained from acutely inflamed versus clinically uninflamed conjunctiva were observed. Developing effective antifibrotic therapies will require understanding of the mechanisms that both induce and maintain the profibrotic phenotype.

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Section: Discussionmentioning

confidence: 99%

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Saw

Schmidt

Offiah

et al. 2011

The American Journal of Pathology

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“…wever, TNFα has been shown to induce expression of TGFβ1 (Churg et al 2002;Sullivan et al 2005). Therefore, it was necessary to determine the extent to which endogenous release of TGFβ1 contributed to the potentiation of LPS plus IFNγ-induced NO production by TNFα.…”

Section: Tnfα and Tgfβ1 Affect Astrocytic No Production Independentlymentioning

confidence: 99%

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Hamby¹,

Gragnolati²,

Hewett³

et al. 2008

Neurochemistry International

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Nitric oxide (NO) synthase-2 (NOS-2), a key source of NO at sites of neuroinflammation, is induced in astrocyte cultures treated with lipopolysaccharide (LPS) plus interferon-γ (IFNγ). A recent study examining the regulation of astrocytic NOS-2 expression demonstrated that transforming growth factor-β1 (TGFβ1) potentiated LPS plus IFNγ-induced NOS-2 expression via expansion of the pool of astrocytes that express NOS-2. Results in the current report indicate that this population-based mechanism of increasing NOS-2 expression is not restricted to TGFβ1, since it also accounts for the potentiation of NO production in astrocyte cultures by tumor necrosis factor-α (TNFα). In contrast to TGFβ1, which required 24 hr preincubation for optimal potentiation of NO production, TNFα was maximally effective when added concurrently with LPS plus IFNγ. Nevertheless, under conditions that optimally potentiated NO production, both cytokines recruited similar numbers of astrocytes to express NOS-2 (% NOS-2-positive cells after LPS plus IFNγ alone or with TNFα or TGFβ1 was 9.5 ± 1.2, 25.3 ± 2.9, and 32.4 ± 3.0, respectively). Interestingly, stimulation of astrocytes in the presence of both TGFβ1 and TNFα additively increased the number of astrocytes that expressed NOS-2 protein (% NOS-2-positive cells was 61.0 ± 4.2) relative to each cytokine alone. Potentiation of NO production by either TNFα or TGFβ1 was not ablated by neutralizing antibodies to TGFβ1 or TNFα, respectively. Thus, the two cytokines act independently to recruit separate pools of astrocytes to express NOS-2. These results are consistent with the notion that astrocytes possess an innate heterogeneity with respect to responsiveness to these cytokines. KeywordsLPS; cytokines; heterogeneity; NO; iNOS; nitric oxide synthase Nitric oxide (NO) is an endogenously derived free radical gas that affects a spectrum of homeostatic and physiologic processes, including blood flow and coagulation, normal brain and heart function, and innate immunity (Belge et al. 2005;Ignarro et al. 1999;MacMicking et al. 1997;Yun et al. 1996). However, it can be harmful under certain pathophysiological conditions. Within the CNS, aberrant NO production has been linked to cerebrovascular dysfunction ( Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NO is derived from L-arginine by the catalytic action of three different NOS isoforms (Stuehr 1999). NOS-1 and -3 are constitutively expressed in neurons and endothelial cells, respectively, and thus were initially termed nNOS and eNOS. In contrast, NOS-2 is not constitutively expressed but can be induced ...

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“…Consistent with that paradigm, we recently reported that a cloned oviduct epithelial cell line responded to infection by C. muridarum with a plethora of cytokines (14), including acute phase cytokines IL-1, IL-6, TNF-␣, GM-CSF, and TGF-␣. These cytokines have been shown to contribute to the pathophysiology of scarring and fibrosis in other systems (21)(22)(23)(24)(25)(26)(27).…”

Section: Pattern Recognition Molecules Activated Bymentioning

confidence: 99%

Pattern Recognition Molecules Activated by Chlamydia muridarum Infection of Cloned Murine Oviduct Epithelial Cell Lines

Derbigny

Kerr

Johnson

2005

The Journal of Immunology

101

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Chlamydia trachomatis is the most common bacterial sexually transmitted disease in the United States and a major cause of female infertility due to infection-induced Fallopian tube scarring. Epithelial cells are likely central to host defense and pathophysiology as they are the principal cell type productively infected by C. trachomatis. We generated cloned murine oviduct epithelial cell lines without viral or chemical transformation to investigate the role of the TLRs and cytosolic nucleotide binding site/leucine-rich repeat proteins Nod1 and Nod2 in epithelial responses to Chlamydia muridarum infection. RT-PCR assays detected mRNA for TLR2 (TLRs 1 and 6), TLR3, and TLR5. No mRNA was detected for TLRs 4, 7, 8, and 9. Messenger RNAs for Nod1 and Nod2 were present in the epithelial cell lines. Oviduct epithelial cell lines infected with C. muridarum or exposed to the TLR2 agonist peptidoglycan secreted representative acute phase cytokines IL-6 and GM-CSF in a MyD88-dependent fashion. Infected epithelial cell lines secreted the immunomodulatory cytokine IFN-β, even though C. muridarum does not have a clear pathogen-associated molecular pattern (PAMP) for triggering IFN-β transcription. The oviduct epithelial lines did not secrete IFN-β in response to the TLR2 agonist peptidoglycan or to the TLR3 agonist poly(I:C). Our data identify TLR2 as the principal TLR responsible for secretion of acute phase cytokines by C. muridarum-infected oviduct epithelial cell lines. The pattern recognition molecule responsible for infection-induced IFN-β secretion by oviduct epithelial cells remains to be determined.

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Tumor Necrosis Factor-α Induces Transforming Growth Factor-β₁Expression in Lung Fibroblasts Through the Extracellular Signal–Regulated Kinase Pathway

Cited by 154 publications

References 47 publications

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Pattern Recognition Molecules Activated by Chlamydia muridarum Infection of Cloned Murine Oviduct Epithelial Cell Lines

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Tumor Necrosis Factor-α Induces Transforming Growth Factor-β1Expression in Lung Fibroblasts Through the Extracellular Signal–Regulated Kinase Pathway

Cited by 154 publications

References 47 publications

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

Profibrotic Phenotype of Conjunctival Fibroblasts from Mucous Membrane Pemphigoid

TGFβ1 and TNFα potentiate nitric oxide production in astrocyte cultures by recruiting distinct subpopulations of cells to express NOS-2

Pattern Recognition Molecules Activated by Chlamydia muridarum Infection of Cloned Murine Oviduct Epithelial Cell Lines

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Tumor Necrosis Factor-α Induces Transforming Growth Factor-β₁Expression in Lung Fibroblasts Through the Extracellular Signal–Regulated Kinase Pathway