Regulation of human airway epithelial cell IL-8 expression by MAP kinases

Li, Jing; Kartha, Sreedharan; Iasvovskaia, Svetlana; Tan, Alan; Bhat, Rajesh K.; Manaligod, Joel M; Page, Kristen; Brasier, Allan R.; Hershenson, Marc B.

doi:10.1152/ajplung.00060.2002

Cited by 130 publications

(136 citation statements)

References 76 publications

(101 reference statements)

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“…The fact that this amount of activated NF-κB, although proven to be partly due to PAR-2 activation, did not lead to secretion of IL-8 as observed in the lower enzyme concentrations puzzled us. Theoretically, as previously mentioned, purified king crab trypsin might be able to cleave PAR-2 both at activation and (Li et al, 2002).…”

Section: Discussionmentioning

confidence: 82%

“…Research indicates that maximal IL-8 protein expression requires activation of NF-κB as well as activation of the MAP kinases ERK, JNK, and p38 (Li et al, 2002). In order to investigate the contribution of MEK/ERK , p38 and NF-κB to the observed secretion of IL-8 and by this to address the observed lack of IL-8 secretion following the generous NF-κB induction in cells stimulated by higher concentrations of purified king crab trypsin, we examined the effects of U0126 (MEK inhibitor), SB202190 (p38 inhibitor), and BAY 11-7082 (NF-κB inhibitor) in PAR-2 agonist peptide, sardine and king crab stimulated A549/NF-κB-luc cells.…”

Section: Il-8 Secretion By Purified Sardine and King Crab Trypsin Stimentioning

confidence: 99%

“…Besides the activation of phospholipase Cβ, formation of inositol triphosphate and diacylglycerol, the receptor is shown to trigger the activation of other downstream signalling pathways including the mitogen-activated protein kinase (MAPK) cascades in distinct cell types. Additionally, studies indicate that maximal interleukin (IL)-8 protein expression requires activation of the MAP kinases ERK, JNK, and p38 as well as activation of the transcription factor NF-κB (Blackwell and Christman, 1997;Gon et al, 1998;Matsumoto et al, 1998;Hashimoto et al, 1999;Chen et al, 2000;Li et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

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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: 82%

Section: Il-8 Secretion By Purified Sardine and King Crab Trypsin Stimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Furthermore, we found that Pen c 13 induced IL-8 release in HAECs via intracellular calcium-regulated ERK activation. Proteases from other allergens, such as cockroach proteases and house dust mite Der p 3, have been shown to elicit IL-8 release by human bronchial epithelial cells via activation of PAR-2 and ERK (5, 35) and recent observations indicate that IL-8 expression in human bronchial epithelial cells requires activation of MAPKs (36,37).…”

Section: Discussionmentioning

confidence: 99%

“…The PAR-1 agonist peptide (SFLLRN), PAR-2 agonist peptide (SLIGKV), PAR-2 reverse peptide (PAR-2 RP; VKGILS), PAR-1 activation site peptide [35][36][37][38][39][40][41][42][43][44][45][46] ), and PAR-2 activation site peptide 32-45 ( 32 SSKGRSLIGKVDGT 45 ) were synthesized by Openbiosystems and purified by reversed HPLC. Abs against amino acids 42-55 of human PAR-1 (ATAP2), amino acids 37-50 of human PAR-2 (SAM11), all forms of ERK 1/2, or phosphorylated ERK 1/2 were obtained from Santa Cruz Biotechnology.…”

Section: Methodsmentioning

confidence: 99%

Mold Allergen, Pen c 13, Induces IL-8 Expression in Human Airway Epithelial Cells by Activating Protease-Activated Receptor 1 and 2

Chiu

Perng

et al. 2007

The Journal of Immunology

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Allergenic serine proteases are important in the pathogenesis of asthma. One of these, Pen c 13, is the immunodominant allergen produced by Penicillium citrinum. Many serine proteases induce cytokine expression, but whether Pen c 13 does so in human respiratory epithelial cells is not known. In this study, we investigated whether Pen c 13 caused IL-8 release and activated protease-activated receptors (PARs) in airway epithelial cells. In airway-derived A549 cells and normal human airway epithelial cells, Pen c 13 induced IL-8 release in a dose-dependent manner. Pen c 13 also increased IL-8 release in a time-dependent manner in A549 cells. Pen c 13 cleaved PAR-1 and PAR-2 at their activation sites. Treatment with Pen c 13 induced intracellular Ca2+ mobilization and desensitized the cells to the action of other proteases and PAR-1 and PAR-2 agonists. Moreover, Pen c 13-mediated IL-8 release was significantly decreased in Ca2+-free medium and was abolished by the protease inhibitors, PMSF and 4-(2-aminoethyl) benzenesulfonyl fluoride. Blocking Abs against the cleavage sites of PAR-1 and PAR-2, but not of PAR-4, inhibited Pen c 13-induced IL-8 production, as did inhibition of phospholipase C. Pen c 13 induced IL-8 expression via activation of ERK 1/2, and not of p38 and JNK. In addition, treatment of A549 cells or normal human airway epithelial cells with Pen c 13 increased phosphorylation of ERK 1/2 by a Ca2+-dependent pathway. These finding show that Pen c 13 induces IL-8 release in airway epithelial cells and that this is dependent on PAR-1 and PAR-2 activation and intracellular calcium.

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