Protein kinase A inhibitors reverse histamine-mediated regulation of IL-5 secretion

• Published in: Immunopharmacology Vol. 39; no. 1; pp. 9 - 19
• Main Authors: Poluektova, Larisa Y., Khan, Manzoor M.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 01.03.1998; Elsevier
• Subjects: Animals; Biological and medical sciences; Bucladesine - pharmacology; Cell Line; Colforsin - pharmacology; Cyclic AMP - analogs & derivatives; Cyclic AMP - metabolism; Cyclic AMP - pharmacology; Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors; D10.G4.1 mouse Th2 helper cells; Fundamental and applied biological sciences. Psychology; Fundamental immunology; H-8; Histamine; Histamine - metabolism; Histamine - pharmacology; Histamine Release - drug effects; Immediate hypersensitivity. Allergy. Anaphylaxis, etc; Immunobiology; Interleukin-5; Interleukin-5 - analysis; Interleukin-5 - secretion; Isoquinolines - pharmacology; Mice; Protein kinase A; Reaction mechanisms, antibodies, chemical mediators; Rp-cAMPS; T-Lymphocytes, Helper-Inducer - drug effects; Thionucleotides - pharmacology; Protein kinase A; H-8, N-[2-(methylaminoethyl]-5-isoquinoline–sulfonamide; Th2, T-helper type 2 cells; PGE2, prostaglandin E2; D10.G4.1 mouse Th2 helper cells; ATP, adenosine 3-phosphate; TGF-β, transforming growth factor-beta; Rp-cAMPS, Rp-diastereomer of adenosine cyclic 3′,5′-phosphorothioate; Interleukin-5; Histamine; cAMP, cyclic adenosine monophosphate; H-8; CTx, cholera toxin; Rp-cAMPS; ConA, concanavalin A; FSK, forskolin; Th1, T-helper type 1 cells; Bt2-cAMP, N6, O2′-dibutiryladenosine 3′5′-cyclic monophosphate; mRNA, messenger ribonucleic acid; PKA, protein kinase A; Immunopathology; Allergy; Enzyme; Transferases; Cytokine; Enzyme inhibitor; Helper cell; In vitro; Interleukin 5; Etiology; Protein kinase; Established cell line; Mechanism of action
• ISSN: 0162-3109
• DOI: 10.1016/S0162-3109(97)00093-3

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.