Proteinase-activated receptor-2–mediated matrix metalloproteinase-9 release from airway epithelial cells

Vliagoftis, Harissios; Schwingshackl, Andreas; Milne, Craig D.; Duszyk, Marek; Hollenberg, Morley D.; Wallace, John L.; Befus, A. Dean; Moqbel, Redwan

doi:10.1067/mai.2000.109058

Cited by 152 publications

(116 citation statements)

References 52 publications

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“…Inhalation of biological particles containing exogenous proteases may produce inflammatory responses in the airways due to activation of PAR-2 mediated reactions. PAR-2 activation on lung epithelial cells is responsible for the release of numerous mediators of inflammation such as IL-8, IL-6, prostaglandin E 2 , matrix-metalloprotease-9 (MMP-9), and granulocyte macrophage-colony stimulating factor (GM-CSF) (Vliagoftis et al, 2000(Vliagoftis et al, , 2001Asokananthan et al, 2002). In this study, we have shown that purified sardine and king crab trypsins are able to induce secretion of the pro-inflammatory cytokine IL-8 from cultured human airway epithelial cells (A549) as previously shown for purified salmon trypsin (Larsen et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

Larsen

Seternes

Bang

2011

Toxicological & Environmental Chemistry

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Respiratory symptoms are present in workers processing a great variety of seafood, including the salmon, sardine, and king crab industry. We have previously shown that salmon trypsin is able to generate DNA-binding of NF-κB and induce secretion of IL-8 from airway epithelial cells by activating PAR-2. In this study we explore if purified trypsins from king crab (Paralithodes camtschaticus) and sardine (Sardinops melanostictus) is able to induce similar effects in cell stimulation assays. Different types of seafood seem to display dissimilar irritant/allergic potencies in human airways and molecular modelling has identified divergent positions in the king crab trypsin compared to salmon trypsin that might influence upon the binding to the N-terminal end of PAR-2, which is a prerequisite for proteolytic activation of the receptor. This knowledge inspired us to investigate if we could detect differences in intracellular signalling pathways coupled to IL-8 in human airway epithelial cells (A549) following stimulation with purified king crab and sardine trypsin. Both sardine and king crab trypsin induce secretion of IL-8 from human airway epithelial cells in a concentration-dependent manner and generate DNA-binding of activated NF-κB. By the use of siRNA we can conclude that these effects are both mediated, at lest partly, through the activation of PAR-2. The king crab and sardine trypsin displays individual differences in transformation of the NF-κB signal, as high enzyme concentrations of king crab trypsin yields high levels of NF-κB that does not translate into increased secretion of IL-8 in the cell stimulation assays. The contribution of MEK/ERK, p38 and NF-κB to the secretion of IL-8 following stimulation with purified sardine and king crab trypsins were explored by the use of specificinhibitors. The results demonstrate that MEK/ERK and NF-κB are both required for purified sardine and king crab trypsin-induced secretion of IL-8 but via separate pathways. P38 was also found to contribute to the secretion of IL-8 by seemingly NF-kB-dependent processes.The data presented indicate that small structural variations in agonists may lead to differences in receptor activation and subsequent intracellular signalling.

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Section: Discussionmentioning

confidence: 99%

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

Larsen

Seternes

Bang

2011

Toxicological & Environmental Chemistry

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“…Many inflammatory cells including eosinophils, lymphocytes and mast cells infiltrate from the circulation to specific sites within asthmatic tissue (Hamid et al, 2003). This leads to structural changes in the airway wall involving smooth muscle hypertrophy, subepithelial deposition of ECM proteins and loss of epithelium (Vliagoftis et al, 2000). Although many studies have focused on the key mediators contributing to these structural changes, much of the detailed mechanism is unknown.…”

Section: Introductionmentioning

confidence: 99%

PMA-induced up-regulation of MMP-9 is regulated by a PKCα-NF-κB cascade in human lung epithelial cells

Shin

Yoon²,

Choe³

et al. 2007

Exp Mol Med

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Expression of matrix metalloproteinase-9 (MMP-9) is associated with airway remodeling and tissue injury in asthma. However, little is known about how MMP-9 is up-regulated in airway epithelial cells. In this study, we show that phorbol myristate acetate (PMA) induces MMP-9 expression via a protein kinase Cα (PKCα)-dependent signaling cascade in BEAS-2B human lung epithelial cells. Pretreatment with either GF109203X, a general PKC inhibitor, or Gö6976, a PKCα/β isozyme inhibitor, inhibited PMA-induced activation of the MMP-9 promoter, as did transient transfection with PKCα antisense oligonuclotides. PMA activated NF-κB by phosphorylating IκB in these cells and this was also inhibited by GF109203X and Gö6976, suggesting that PKCα acts as an upstream regulator of NF-κB in PMA-induced MMP-9 induction. Our results indicate that a "PKCα-NF-κB"-dependent cascade is involved in the signaling leading to PMA-induced MMP-9 expression in the lung epithelium.

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“…Abbreviations: em, embryo; VP, ventral prostate; DP, dorsal prostate; LP, lateral prostate; AP, anterior prostate; BUG, bulbourethral gland; vas, vas deferens; epi, epididymis; ampu, ampullary gland; ugs, urogenital sinus. epithelial cell line (44). Given these results along with the overlapping expression of PAR1 and PAR2 in the kidney (6,10) and prostate (48), we examined whether the loss TMPRSS2 protease activity in vivo modulated the transcript levels of Par1, Par2, Mmp2, and Mmp9.…”

Section: Expression Of Protease-activated Receptors In Tmprss2mentioning

confidence: 99%

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

Kim¹,

Heinlein²,

Hackman

et al. 2006

Molecular and Cellular Biology

218

193

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Tmprss2 encodes an androgen-regulated type II transmembrane serine protease (TTSP) expressed highly in normal prostate epithelium and has been implicated in prostate carcinogenesis. Although in vitro studies suggest protease-activated receptor 2 may be a substrate for TMPRSS2, the in vivo biological activities of TMPRSS2 remain unknown. We generated Tmprss2 ؊/؊ mice by disrupting the serine protease domain through homologous recombination. Compared to wild-type littermates, Tmprss2 ؊/؊ mice developed normally, survived to adulthood with no differences in protein levels of prostatic secretions, and exhibited no discernible abnormalities in organ histology or function. Loss of TMPRSS2 serine protease activity did not influence fertility, reduce survival, result in prostate hyperplasia or carcinoma, or alter prostatic luminal epithelial cell regrowth following castration and androgen replacement. Lack of an observable phenotype in Tmprss2 ؊/؊ mice was not due to transcriptional compensation by closely related Tmprss2 homologs. We conclude that the lack of a discernible phenotype in Tmprss2 ؊/؊ mice suggests functional redundancy involving one or more of the type II transmembrane serine protease family members or other serine proteases. Alternatively, TMPRSS2 may contribute a specialized but nonvital function that is apparent only in the context of stress, disease, or other systemic perturbation.

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Proteinase-activated receptor-2–mediated matrix metalloproteinase-9 release from airway epithelial cells

Cited by 152 publications

References 52 publications

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

Purified sardine and king crab trypsin display individual differences in PAR-2-, NF-κB-, and IL-8 signaling

PMA-induced up-regulation of MMP-9 is regulated by a PKCα-NF-κB cascade in human lung epithelial cells

Phenotypic Analysis of Mice Lacking the Tmprss2-Encoded Protease

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