PROTEIN-KINASE-A INHIBITORS REVERSE HISTAMINE-MEDIATED REGULATION OF IL-5 SECRETION

Histamine and IL-5 are important autacoid mediators involved in the et iology of allergic diseases. IL-5 is the main factor of eosinophilic r eactions in allergy. It has been suggested that the protein kinase A-d ependent (PKA) pathway of signal transduction may play the main role i n histamine-induced elevation of interleukin-5 production. This study was designed to investigate the effects of the inhibitors of regulator y 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 Th, he lper cell Line. Pretreatment of this cell line with histamine at a con centration of 10(-4) M for 6-9 h had the maximum stimulatory effects ( 226-420%) on IL-5 production. Other cAMP-elevating agents including fo rskolin and Bt(2)-cAMP produced similar effects. The PKA inhibitors N- [2-(methylaminoethyl]-5-isoquinoline-sulfonate (H-8) and Rp-diastereom er of adenosine cyclic 3',5'-phosphorothioate (Rp-cAMPS) were used for the inhibition of catalytic and regulatory subunits of PKA, respectiv ely. 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 histami ne-induced stimulation. Neither inhibitor affected IL-5 production whe n tested alone. These observations suggest a role for PKA in histamine -mediated increase in IL-5 production. (C) 1998 Elsevier Science B.V.