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NF ‐κ B ‐dependent IL ‐8 induction by prostaglandin E 2 receptors EP 1 and EP 4
Author(s) -
NeuschäferRube F,
PatheNeuschäferRube A,
Hippenstiel S,
Kracht M,
Püschel GP
Publication year - 2013
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02182.x
Subject(s) - hek 293 cells , receptor , microbiology and biotechnology , agonist , chemistry , messenger rna , biology , biochemistry , gene
Background and Purpose Recent studies suggested a role for PGE 2 in the expression of the chemokine IL ‐8. PGE 2 signals via four different GPCRs , EP 1 ‐EP 4 . The role of EP 1 and EP 4 receptors for IL ‐8 induction was studied in HEK 293 cells, overexpressing EP 1 ( HEK‐EP 1 ), EP 4 ( HEK‐EP 4 ) or both receptors ( HEK ‐ EP 1 + EP 4 ). Experimental Approach IL ‐8 mRNA and protein induction and IL ‐8 promoter and NF ‐κ B activation were assessed in EP expressing HEK cells. Key Results In HEK‐EP 1 and HEK ‐ EP 1 + EP 4 but not HEK or HEK ‐ EP 4 cells, PGE 2 activated the IL ‐8 promoter and induced IL ‐8 mRNA and protein synthesis. Stimulation of HEK ‐ EP 1 + EP 4 cells with an EP 1 ‐specific agonist activated IL ‐8 promoter and induced IL ‐8 mRNA and protein, whereas a specific EP 4 agonist neither activated the IL ‐8 promoter nor induced IL ‐8 mRNA and protein synthesis. Simultaneous stimulation of HEK ‐ EP 1 + EP 4 cells with both agonists activated IL ‐8 promoter and induced IL ‐8 mRNA to the same extent as PGE 2 . In HEK ‐ EP 1 + EP 4 cells, PGE 2 ‐mediated IL ‐8 promoter activation and IL ‐8 mRN A induction were blunted by inhibition of IκB kinase. PGE 2 activated NF ‐κ B in HEK‐EP 1 , HEK‐EP 4 and HEK ‐ EP 1 + EP 4 cells. In HEK ‐ EP 1 + EP 4 cells, simultaneous activation of both receptors was needed for maximal PGE 2 ‐induced NF ‐κ B activation. PGE 2 ‐stimulated NF ‐κ B activation by EP 1 was blocked by inhibitors of PLC , calcium‐signalling and S rc‐kinase, whereas that induced by EP 4 was only blunted by S rc‐kinase inhibition. Conclusions and Implications These findings suggest that PGE 2 ‐mediated NF ‐κ B activation by simultaneous stimulation of EP 1 and EP 4 receptors induces maximal IL ‐8 promoter activation and IL ‐8 mRNA and protein induction.