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.