Regulation of interleukin-13 by type 4 cyclic nucleotide phosphodiesterase (PDE) inhibitors in allergen-specific human T lymphocyte clones.
Interleukin-13 (IL-13) is a proinflammatory cytokine of T cell origin. Structural and functional studies suggest a key role for IL-13 in the genesis of chronic allergic inflammation; as such, its pharmacologic inhibition is of potential clinical utility. We studied the pharmacologic regulation of IL-13 expression by cyclic nucleotide phosphodiesterase (PDE) inhibitors in a panel of Amb a 1 (a major allergen of short ragweed, Ambrosia artemisiifolia)-specific T cell clones derived from a ragweed allergic, asthmatic subject. Proliferative responses of these cells were down-regulated by rolipram, a PDE4 inhibitor (% inhibitionMAX = 67%; IC50 = 20 microM). While the PDE3 inhibitor siguazodan provided no independent efficacy (IC50 > 10(-4) M), an increased efficacy of rolipram in the presence of 10(-5) M siguazodan was noted at 10(-6), 10(-5), and 10(-4) M rolipram (P < 0.03, 0.01, and 0.04, respectively). The EC50 values remained unchanged between assays using the PDE4 inhibitor with or without the PDE3 inhibitor. Both IL-13 gene expression and protein secretion into culture supernatants were down-regulated by the PDE4 inhibitor (P < or = 0.005). Once again, the use of a PDE3 inhibitor provided no independent efficacy (P > or = 0.2), and in this instance, increased efficacy of the PDE4 inhibitor with the PDE3 inhibitor was not apparent (P > or = 0.3). IL-13 production from clones with Th0, Th1, and Th2 phenotypes appeared equally sensitive to treatment with the PDE4 inhibitor. We conclude that the anti-inflammatory effects of PDE4 inhibitors may be mediated, in part, by down-regulation of IL-13.
Essayan
D M
DM
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, U.S.A.
Kagey-Sobotka
A
A
Lichtenstein
L M
LM
Huang
S K
SK
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000485:Allergens; D002999:Clone Cells; D015870:Gene Expression; D006023:Glycoproteins / Q000494:pharmacology*; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D018793:Interleukin-13 / Q000096:biosynthesis* / Q000235:genetics; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000187:drug effects* / Q000276:immunology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram
D000485:Allergens; D006023:Glycoproteins; D006146:Guanidines; D018793:Interleukin-13; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; C056215:siguazodan; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram