Salbutamol inhibits trypsin-mediated production of CXCL8 by keratinocytes.
Treatment of primary keratinocytes (HEKAp) with trypsin led to the production and release of CXCL8. Production of CXCL8 was exquisitely sensitive to inhibition by co-treatment with the beta(2) agonist sabutamol (IC(50)=1.1 nM). The inhibitory effect of salbutamol was beta receptor-mediated since the effect was prevented by the beta antagonist sotalol. Salbutamol also elevated intracellular levels of cAMP (EC(50)=82 nM) but the relationship to the inhibition of CXCL8 secretion was not clear-cut since much higher concentrations of salbutamol were required to elevate total cellular cAMP than inhibit CXCL8 production. However, the effect of salbutamol is likely to be mediated by elevation of cAMP since forskolin, an adenylyl cyclase activator, mimicked the effects of salbutamol while the adenylyl cyclase inhibitor 2',5'-dideoxyadenosine inhibited the effects of salbutamol. Potentiation of cAMP production by co-treatment with the phosphodiesterase type 4 inhibitor rolipram only marginally enhanced the inhibitory effect of salbutamol on CXCL8 production. Taken together, these data suggest that elevation of cAMP production is required for the inhibitory effect of salbutamol on CXCL8 production by keratinocytes and that low threshold levels of cAMP are sufficient to mediate this effect.
Wettey
Frank R
FR
Oxagen Limited, 91 Milton Park, Abingdon, Oxon OX14 4RY, UK.
Xue
Luzheng
L
Pettipher
Roy
R
D000262:Adenylyl Cyclases / Q000378:metabolism; D000420:Albuterol / Q000494:pharmacology*; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D016048:Dideoxyadenosine / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis* / Q000378:metabolism; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D014357:Trypsin / Q000378:metabolism*
C508606:CXCL8 protein, human; D016209:Interleukin-8; D005576:Colforsin; D016048:Dideoxyadenosine; C021008:2',5'-dideoxyadenosine; D000242:Cyclic AMP; D014357:Trypsin; D000262:Adenylyl Cyclases; D020889:Rolipram; D000420:Albuterol