Signal Transduction Pathways (Mapks, Nf-Kappa B, And C/Ebp) Regulating Cox-2 Expression In Nasal Fibroblasts From Asthma Patients With Aspirin Intolerance

Background: Recent studies have revealed that cyclooxygenase-2 (COX-2) expression is down-regulated in aspirin-induced asthma (AIA). Various signal pathways (MAPKs, NF-kappa B and C/EBP) are involved in COX-2 regulation.Objective: To investigate the regulation of COX-2 expression through MAP-kinase pathway activation and nuclear factor translocation in aspirin-induced asthma (AIA).Methods: Fibroblasts were isolated from specimens of nasal mucosa (NM, N = 5) and nasal polyps (NP, N = 5). After IL-1 beta (1 ng/ml) incubation, COX-2 and phosphorylated forms of ERK, JNK and p38 MAPK were measured by Western blot. MAPK's role in IL-1 beta-induced COX-2 expression was assessed by treating cells with ERK (PD98059), JNK (SP600125) and p38 MAPK (SB203580) inhibitors (0.1-10 mM) prior to IL-1 beta exposure. NF-kappa B and C/EBP nuclear translocation was measured by Western blot and TransAM (R) after IL-1 beta (10 ng/ml) exposure.Results: No differences were observed in the MAPK phosphorylation time-course between NM and NP-AIA fibroblasts. The p38 MAPK inhibitor at 10 mM significantly reduced IL-1 beta-induced COX-2 expression in NM fibroblasts (85%). In NP-AIA fibroblasts the COX-2 inhibition (65%) at 1 and 10 mM was not statistically significant compared to non-treated cells. ERK and JNK inhibitors had no significant effect in either the NM or NP-AIA cultures. The effect of IL-1 beta on NF-kappa B and C/EBP subunits' nuclear translocation was similar between NM and NP-AIA fibroblasts.Conclusions: These results suggest that p38 MAPK is the only MAPK involved in IL-1 beta-induced COX-2 expression. NM and NP-AIA fibroblasts have similar MAPK phosphorylation dynamics and nuclear factor translocation (NF-kappa B and C/EBP). COX-2 downregulation observed in AIA patients appears not to be caused by differences in MAPK dynamics or transcription factor translocation.