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PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium.
Clin Exp Allergy 2007; 37(7):1009-22CE

Abstract

BACKGROUND

The effects of protease-activated receptor-2 (PAR-2) stimulation on inflammation mechanisms of chronic rhinosinusitis (CRS) are still unknown.

METHODS

PAR-2 receptor expression was investigated by immunohistochemistry and Taqman mRNA analysis in the mucosa of different rhinosinusitis entities. In primary nasal epithelial cell cultures, the function of PAR-2 and its ability to produce CXC, CC chemokines, and IL-6 were measured by calcium mobilization and stimulation tests. Inhibition tests were performed using cortisone, serine protease inhibitors, cysteine protease inhibitors, Pertussis toxin (PTX) and nuclear transcription factor (NF-kappaB) inhibition (BAY 11-7085). Signal transduction pathways were analysed by electromobility shift assays (EMSA) and NF-kappaB binding studies.

RESULTS

The expression of PAR-2 was found to be increased in CRS specimens. The activation of PAR by trypsin or PAR-2-specific activating peptide (AP) caused an increase in cytosolic calcium, as well as the release of the CXC chemokines IL-8 and growth-related oncogene (GRO)-alpha, but not the release of CC chemokines or IL-6. AP-induced CXC chemokine was sensitive to PTX and activation of NF-kappaB was inhibited by BAY11-7085. Furthermore, a serine protease inhibitor significantly inhibited chemokine synthesis stimulated by trypsin and culture supernatants of staphylococci, whereas steroids and cysteine protease inhibitors had little effect.

CONCLUSION

PAR-2 plays a role in serine protease-mediated regulation - staphylococcal and non-staphylococcal origin - of IL-8 and GRO-alpha in nasal epithelial cells, but not in the regulation of CC chemokines. PAR-2 may therefore be involved in the pathophysiology of CRS and NP at different sites of activation, namely (i) proteases, (ii) the PAR-2 receptor itself or (iii) the application of novel agents that block NF-kappaB/IkappaB-alpha signalling.

Authors+Show Affiliations

Department of Otorhinolaryngology, Head and Neck Surgery, IZK Münster and Boltzmann Institute for Immunobiology of the Skin, Münster, Germany. rudack@uni-muenster.deNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

17581194

Citation

Rudack, C, et al. "PAR-2 Activation Regulates IL-8 and GRO-alpha Synthesis By NF-kappaB, but Not RANTES, IL-6, Eotaxin or TARC Expression in Nasal Epithelium." Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, vol. 37, no. 7, 2007, pp. 1009-22.
Rudack C, Steinhoff M, Mooren F, et al. PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium. Clin Exp Allergy. 2007;37(7):1009-22.
Rudack, C., Steinhoff, M., Mooren, F., Buddenkotte, J., Becker, K., von Eiff, C., & Sachse, F. (2007). PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium. Clinical and Experimental Allergy : Journal of the British Society for Allergy and Clinical Immunology, 37(7), pp. 1009-22.
Rudack C, et al. PAR-2 Activation Regulates IL-8 and GRO-alpha Synthesis By NF-kappaB, but Not RANTES, IL-6, Eotaxin or TARC Expression in Nasal Epithelium. Clin Exp Allergy. 2007;37(7):1009-22. PubMed PMID: 17581194.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - PAR-2 activation regulates IL-8 and GRO-alpha synthesis by NF-kappaB, but not RANTES, IL-6, eotaxin or TARC expression in nasal epithelium. AU - Rudack,C, AU - Steinhoff,M, AU - Mooren,F, AU - Buddenkotte,J, AU - Becker,K, AU - von Eiff,C, AU - Sachse,F, PY - 2007/6/22/pubmed PY - 2007/10/12/medline PY - 2007/6/22/entrez SP - 1009 EP - 22 JF - Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology JO - Clin. Exp. Allergy VL - 37 IS - 7 N2 - BACKGROUND: The effects of protease-activated receptor-2 (PAR-2) stimulation on inflammation mechanisms of chronic rhinosinusitis (CRS) are still unknown. METHODS: PAR-2 receptor expression was investigated by immunohistochemistry and Taqman mRNA analysis in the mucosa of different rhinosinusitis entities. In primary nasal epithelial cell cultures, the function of PAR-2 and its ability to produce CXC, CC chemokines, and IL-6 were measured by calcium mobilization and stimulation tests. Inhibition tests were performed using cortisone, serine protease inhibitors, cysteine protease inhibitors, Pertussis toxin (PTX) and nuclear transcription factor (NF-kappaB) inhibition (BAY 11-7085). Signal transduction pathways were analysed by electromobility shift assays (EMSA) and NF-kappaB binding studies. RESULTS: The expression of PAR-2 was found to be increased in CRS specimens. The activation of PAR by trypsin or PAR-2-specific activating peptide (AP) caused an increase in cytosolic calcium, as well as the release of the CXC chemokines IL-8 and growth-related oncogene (GRO)-alpha, but not the release of CC chemokines or IL-6. AP-induced CXC chemokine was sensitive to PTX and activation of NF-kappaB was inhibited by BAY11-7085. Furthermore, a serine protease inhibitor significantly inhibited chemokine synthesis stimulated by trypsin and culture supernatants of staphylococci, whereas steroids and cysteine protease inhibitors had little effect. CONCLUSION: PAR-2 plays a role in serine protease-mediated regulation - staphylococcal and non-staphylococcal origin - of IL-8 and GRO-alpha in nasal epithelial cells, but not in the regulation of CC chemokines. PAR-2 may therefore be involved in the pathophysiology of CRS and NP at different sites of activation, namely (i) proteases, (ii) the PAR-2 receptor itself or (iii) the application of novel agents that block NF-kappaB/IkappaB-alpha signalling. SN - 0954-7894 UR - https://www.unboundmedicine.com/medline/citation/17581194/PAR_2_activation_regulates_IL_8_and_GRO_alpha_synthesis_by_NF_kappaB_but_not_RANTES_IL_6_eotaxin_or_TARC_expression_in_nasal_epithelium_ L2 - https://doi.org/10.1111/j.1365-2222.2007.02686.x DB - PRIME DP - Unbound Medicine ER -