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Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase.
J Allergy Clin Immunol. 2003 Dec; 112(6):1112-8.JA

Abstract

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.

Authors+Show Affiliations

Department of Pediatrics, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.No affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

14657869

Citation

Page, Kristen, et al. "Cockroach Proteases Increase IL-8 Expression in Human Bronchial Epithelial Cells Via Activation of Protease-activated Receptor (PAR)-2 and Extracellular-signal-regulated Kinase." The Journal of Allergy and Clinical Immunology, vol. 112, no. 6, 2003, pp. 1112-8.
Page K, Strunk VS, Hershenson MB. Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase. J Allergy Clin Immunol. 2003;112(6):1112-8.
Page, K., Strunk, V. S., & Hershenson, M. B. (2003). Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase. The Journal of Allergy and Clinical Immunology, 112(6), 1112-8.
Page K, Strunk VS, Hershenson MB. Cockroach Proteases Increase IL-8 Expression in Human Bronchial Epithelial Cells Via Activation of Protease-activated Receptor (PAR)-2 and Extracellular-signal-regulated Kinase. J Allergy Clin Immunol. 2003;112(6):1112-8. PubMed PMID: 14657869.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cockroach proteases increase IL-8 expression in human bronchial epithelial cells via activation of protease-activated receptor (PAR)-2 and extracellular-signal-regulated kinase. AU - Page,Kristen, AU - Strunk,Valerie S, AU - Hershenson,Marc B, PY - 2003/12/6/pubmed PY - 2004/1/24/medline PY - 2003/12/6/entrez SP - 1112 EP - 8 JF - The Journal of allergy and clinical immunology JO - J. Allergy Clin. Immunol. VL - 112 IS - 6 N2 - 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. SN - 0091-6749 UR - https://www.unboundmedicine.com/medline/citation/14657869/Cockroach_proteases_increase_IL_8_expression_in_human_bronchial_epithelial_cells_via_activation_of_protease_activated_receptor__PAR__2_and_extracellular_signal_regulated_kinase_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0091674903022656 DB - PRIME DP - Unbound Medicine ER -