A role for whey acidic protein four-disulfide-core 12 (WFDC12) in the regulation of the inflammatory response in the lung

Glasgow, Arlene; Small, D.; Scott, Aaron; McLean, Denise; Camper, N. D.; Hamid, Umar Imran; Hegarty, Shauna; Parekh, Dhruv; O'Kane, Cecilia M; Lundy, Fionnuala T.; McNally, Paul; Elborn, J. Stuart; McAuley, Daniel F.; Weldon, Sinéad; Taggart, Clifford C.

doi:10.1136/thoraxjnl-2014-206488

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…After 16 h of LPS treatment, TLR-4 showed a slight increase, indicating that it is essential for the activation of the immune response induced by LPS. It has been reported that activation of TLR4 by its principal agonist, LPS, results in an immunostimulatory intracellular signaling pathway leading to the activation of the transcriptional factor, NFκB [ 12 ]. Our data show that TLR4 expression was inhibited by shWfdc21, and then responded rapidly to LPS stimulation.…”

Section: Discussionmentioning

confidence: 99%

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Whey Acidic Protein/Four-Disulfide Core Domain 21 Regulate Sepsis Pathogenesis in a Mouse Model and a Macrophage Cell Line via the Stat3/Toll-Like Receptor 4 (TLR4) Signaling Pathway

Xie¹,

Guo²,

Liu³

2018

Med Sci Monit

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BackgroundWhey acidic protein/four-disulfide core domain 21 (Wfdc21), also known as Lnc-DC, it has been reported to be correlated with immune response. However, the role of Wfdc21 in the pathogenesis of sepsis is still unknown. In the present study, we aimed to investigate the role of Wfdc21 in the pathogenesis of sepsis.Material/MethodsThe cecal ligation and puncture (CLP)-induced sepsis model was established in Balb/c mice. Animals were euthanized 4, 8, 16, or 24 h after CLP. The glycogen distribution in the kidney and liver was checked by Periodic acid-Schiff (PAS) staining. Changes in the serum interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) concentrations were monitored with ELISA, and Wdfc21 expression was determined by qPCR. Mouse macrophage-like RAW264.7 cells were treated with different doses of lipopolysaccharide (LPS) from Escherichia coli to mimic sepsis in vitro. Western blot analysis was performed to confirm whether LPS-induced in vitro sepsis was correlated with the involvement of the Stat3/TLR4 signaling pathway. In addition, RAW 264.7 cells were infected with lentiviruses containing Wfdc21 shRNA to further confirm the role of Wfdc21 in the pathogenesis of sepsis.ResultsWe found that Wfdc21 level was elevated in the CLP-induced animal model and LPS-treated RAW264.7 cells. Furthermore, the downregulation of Wfdc21 modulated the concentration of pro-inflammatory factors in LPS-treated macrophages, such as IL-1β and TNF-α, in LPS-treated macrophages. This regulatory effect was mediated through the Stat3/TLR4 signaling pathway, since Wfdc21 can regulate p-Stat3 and TLR4 levels in LPS-treated macrophages.ConclusionsWfdc21 plays a critical role in the pathogenesis of sepsis and may provide a therapeutic target for sepsis treatment.

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Section: Discussionmentioning

confidence: 99%

“…Wfdc family members are critical in occurrence of inflammation. In the lungs, Wfdc12 regulates the inflammatory response [ 12 ]. Wfdc1 is a key modulator of inflammatory and wound repair responses.…”

Section: Introductionmentioning

confidence: 99%

Whey Acidic Protein/Four-Disulfide Core Domain 21 Regulate Sepsis Pathogenesis in a Mouse Model and a Macrophage Cell Line via the Stat3/Toll-Like Receptor 4 (TLR4) Signaling Pathway

Xie¹,

Guo²,

Liu³

2018

Med Sci Monit

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“…SLPI is up-regulated in the epidermis of psoriasis patients and in injured skin and is induced during the proliferation of keratinocytes [ 31 ]. On the other hand, WFDC12 is a member of the whey acidic protein (WAP) family [ 32 ] and WFDC12 levels in bronchoalveolar lavage fluid are increased in inflammatory respiratory conditions [ 33 ]. The roles of SLPI and Wfdc12 in the skin are not fully understood, but the up-regulation of those proteins in TGM1 deficiency might contribute to innate defense responses of the skin through anti-protease, anti-microbial and/or anti-inflammatory activities.…”

Section: Discussionmentioning

confidence: 99%

Activation of Molecular Signatures for Antimicrobial and Innate Defense Responses in Skin with Transglutaminase 1 Deficiency

et al. 2016

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Mutations of the transglutaminase 1 gene (TGM1) are a major cause of autosomal recessive congenital ichthyoses (ARCIs) that are associated with defects in skin barrier structure and function. However, the molecular processes induced by the transglutaminase 1 deficiency are not fully understood. The aim of the present study was to uncover those processes by analysis of cutaneous molecular signatures. Gene expression profiles of wild-type and Tgm1–/–epidermis were assessed using microarrays. Gene ontology analysis of the data showed that genes for innate defense responses were up-regulated in Tgm1–/–epidermis. Based on that result, the induction of Il1b and antimicrobial peptide genes, S100a8, S100a9, Defb14, Camp, Slpi, Lcn2, Ccl20 and Wfdc12, was confirmed by quantitative real-time PCR. A protein array revealed that levels of IL-1β, G-CSF, GM-CSF, CXCL1, CXCL2, CXCL9 and CCL2 were increased in Tgm1–/–skin. Epidermal growth factor receptor (EGFR) ligand genes, Hbegf, Areg and Ereg, were activated in Tgm1–/–epidermis. Furthermore, the antimicrobial activity of an epidermal extract from Tgm1–/–mice was significantly increased against both Escherichia coli and Staphylococcus aureus. In the epidermis of ichthyosiform skins from patients with TGM1 mutations, S100A8/9 was strongly positive. The expression of those antimicrobial and defense response genes was also increased in the lesional skin of an ARCI patient with TGM1 mutations. These results suggest that the up-regulation of molecular signatures for antimicrobial and innate defense responses is characteristic of skin with a transglutaminase 1 deficiency, and this autonomous process might be induced to reinforce the defective barrier function of the skin.

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“…Ethical approval for the use of these samples was obtained from the Queen's University Belfast School of Medicine, Dentistry and Biomedical Science Research Ethics Committee (Belfast, UK). The lungs were perfused ex vivo based on previously described methods [32,33]. Experimentation ceased 4 h after LPS instillation, upon which tissue samples for histology were taken from LPS-perfused lobes [32].…”

Section: Human Lung Tissuementioning

confidence: 99%

“…The lungs were perfused ex vivo based on previously described methods [32,33]. Experimentation ceased 4 h after LPS instillation, upon which tissue samples for histology were taken from LPS-perfused lobes [32]. Lung tissue sections from CF patients were obtained from the University of Newcastle (Newcastle upon Tyne, UK).…”

Section: Human Lung Tissuementioning

confidence: 99%

Characterisation of eppin function: expression and activity in the lung

et al. 2017

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Eppin is a serine protease inhibitor expressed in male reproductive tissues.The aim of this study was to investigate the localisation and regulation of eppin expression in myeloid and epithelial cell lines, and explore its potential role as a multifunctional host defence protein.Using immunohistochemistry and Western blotting, eppin was detected in the lungs of patients with acute respiratory distress syndrome and cystic fibrosis lung disease. Expression of eppin in monocytic cells was unaffected by stimulation with Toll-like receptor agonists, cytokines and hormone receptor agonists. However, upregulated expression and secretion of eppin was observed following treatment of monocytes with epidermal growth factor. Incubation of recombinant eppin with monocytic cells resulted in significant inhibition of lipopolysaccharide-induced chemokine production. Furthermore, eppin inhibited lipopolysaccharide-induced NF-κB activation by a mechanism which involved accumulation of phosphorylated IκBα. In an model of lung inflammation induced by lipopolysaccharide, eppin administration resulted in decreased recruitment of neutrophils to the lung with a concomitant reduction in the levels of the neutrophil chemokine macrophage inflammatory protein-2.Overall, these results suggest a role for eppin outside of the reproductive tract and that eppin may have a role in the innate immune response in the lung.

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A role for whey acidic protein four-disulfide-core 12 (WFDC12) in the regulation of the inflammatory response in the lung

Cited by 17 publications

References 31 publications

Whey Acidic Protein/Four-Disulfide Core Domain 21 Regulate Sepsis Pathogenesis in a Mouse Model and a Macrophage Cell Line via the Stat3/Toll-Like Receptor 4 (TLR4) Signaling Pathway

Whey Acidic Protein/Four-Disulfide Core Domain 21 Regulate Sepsis Pathogenesis in a Mouse Model and a Macrophage Cell Line via the Stat3/Toll-Like Receptor 4 (TLR4) Signaling Pathway

Activation of Molecular Signatures for Antimicrobial and Innate Defense Responses in Skin with Transglutaminase 1 Deficiency

Characterisation of eppin function: expression and activity in the lung

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