PMID- 14657869
OWN - NLM
STAT- MEDLINE
DCOM- 20040123
LR  - 20091119
IS  - 0091-6749 (Print)
IS  - 0091-6749 (Linking)
VI  - 112
IP  - 6
DP  - 2003 Dec
TI  - Cockroach proteases increase IL-8 expression in human bronchial epithelial cells 
      via activation of protease-activated receptor (PAR)-2 and 
      extracellular-signal-regulated kinase.
PG  - 1112-8
AB  - BACKGROUND: We have shown that serine proteases in German cockroach extract 
      increase TNF-alpha-induced expression of IL-8 in human bronchial epithelial 
      cells. The mechanism by which cockroach proteases regulate cytokine expression is 
      unknown; however, protease-activated receptors (PARs) might play a role. 
      OBJECTIVE: We sought to determine the role of PARs and 
      extracellular-signal-regulated kinase (ERK) in cockroach-induced regulation of 
      IL-8 expression. METHODS: 16HBE14o- human bronchial epithelial cells were treated 
      with the specific PAR-1 and PAR-2 agonists, TFRIFD and SLIGKV, respectively. IL-8 
      transcription was assessed by transiently transfecting cells with a 
      luciferase-tagged IL-8 promoter construct, and in some cases, dominant-negative 
      expression vectors. To block PAR cleavage, antibodies against the cleavage region 
      of PAR-1 and PAR-2 were used. ERK phosphorylation was determined by Western blot. 
      RESULTS: Although both PAR-1 and PAR-2 were endogenously expressed in 16HBE14o- 
      cells, selective activation of PAR-2 but not PAR-1 mimicked the effect of 
      cockroach extract on IL-8 expression. Using a blocking antibody against cleavage 
      of PAR-2 but not PAR-1 attenuated cockroach-extract-induced responses, suggesting 
      that cockroach proteases cleave PAR-2. Treatment of cells with cockroach extract 
      and SLIGKV each increased phosphorylation of ERK. Chemical or genetic inhibition 
      of Ras and mitogen-activated protein kinase/ERK (MEK), upstream activators of 
      ERK, each attenuated cockroach- and PAR-2-induced IL-8 transcription. CONCLUSION: 
      Cockroach proteases and PAR-2 activation synergistically increase 
      TNF-alpha-induced IL-8 transcription via activation of ERK. These data suggest an 
      important role for PAR-2 and ERK activation in the regulation of cytokine 
      expression in airway epithelium in response to cockroach proteases.
FAU - Page, Kristen
AU  - Page K
AD  - Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH 45229, 
      USA.
FAU - Strunk, Valerie S
AU  - Strunk VS
FAU - Hershenson, Marc B
AU  - Hershenson MB
LA  - eng
GR  - HL56399/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - J Allergy Clin Immunol
JT  - The Journal of allergy and clinical immunology
JID - 1275002
RN  - 0 (Allergens)
RN  - 0 (Interleukin-8)
RN  - 0 (Receptor, PAR-2)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinases)
RN  - EC 3.4.- (Endopeptidases)
RN  - EC 3.6.5.2 (ras Proteins)
SB  - IM
MH  - Allergens/immunology
MH  - Animals
MH  - Bronchi/cytology/*immunology
MH  - Cell Line
MH  - Cockroaches/enzymology/*immunology
MH  - Endopeptidases/immunology/*pharmacology
MH  - Epithelial Cells/*immunology
MH  - Humans
MH  - Interleukin-8/genetics/*metabolism
MH  - Mitogen-Activated Protein Kinases/metabolism
MH  - Promoter Regions, Genetic
MH  - Receptor, PAR-2/*metabolism
MH  - Transcription, Genetic
MH  - Tumor Necrosis Factor-alpha/metabolism
MH  - ras Proteins/metabolism
EDAT- 2003/12/06 05:00
MHDA- 2004/01/24 05:00
CRDT- 2003/12/06 05:00
PHST- 2003/12/06 05:00 [pubmed]
PHST- 2004/01/24 05:00 [medline]
PHST- 2003/12/06 05:00 [entrez]
AID - S0091674903022656 [pii]
AID - 10.1016/j.jaci.2003.08.050 [doi]
PST - ppublish
SO  - J Allergy Clin Immunol. 2003 Dec;112(6):1112-8. doi: 10.1016/j.jaci.2003.08.050.