Protein kinase A inhibitors reverse histamine-mediated regulation of IL-5 secretion.
Histamine and IL-5 are important autacoid mediators involved in the etiology of allergic diseases. IL-5 is the main factor of eosinophilic reactions in allergy. It has been suggested that the protein kinase A-dependent (PKA) pathway of signal transduction may play the main role in histamine-induced elevation of interleukin-5 production. This study was designed to investigate the effects of the inhibitors of regulatory and catalytic subunits of PKA on histamine-mediated elevation of IL-5 production. In our study, histamine at a concentration range of 10(-4)-10(-6) M enhanced IL-5 production in D10.G4.1 cells, a mouse Th2 helper cell line. Pretreatment of this cell line with histamine at a concentration of 10(-4) M for 6-9 h had the maximum stimulatory effects (226-420%) on IL-5 production. Other cAMP-elevating agents including forskolin and Bt2-cAMP produced similar effects. The PKA inhibitors N-[2-(methylaminoethyl]-5-isoquinoline-sulfonamide (H-8) and Rp-diastereomer of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS) were used for the inhibition of catalytic and regulatory subunits of PKA, respectively. Pretreatment of D10.G4.1 cells with H-8 at a concentration of 10(-5) M completely prevented the effects of histamine at a concentration range of 10(-6)-10(-4) M. Rp-cAMPS at 10(-5) M also prevented histamine-induced stimulation. Neither inhibitor affected IL-5 production when tested alone. These observations suggest a role for PKA in histamine-mediated increase in IL-5 production.
Department of Pharmaceutical and Adm. Sciences, Creighton University, Omaha, NE 68178, USA.
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Poluektova
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Khan
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D006632:Histamine / Q000378:metabolism / Q000494:pharmacology*; D006636:Histamine Release / Q000187:drug effects*; D015848:Interleukin-5 / Q000032:analysis / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology*; D051379:Mice; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*; D013873:Thionucleotides / Q000494:pharmacology
D015848:Interleukin-5; D007546:Isoquinolines; D013873:Thionucleotides; D005576:Colforsin; C016957:adenosine-3',5'-cyclic phosphorothioate; D003994:Bucladesine; D006632:Histamine; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases