DIFFERENTIAL INVITRO REGULATION BY GLUCOCORTICOIDS OF MONOCYTE-DERIVED CYTOKINE GENERATION IN GLUCOCORTICOID-RESISTANT BRONCHIAL-ASTHMA

We previously described a 3 kD neutrophil priming activity (NPA) derived from peripheral blood monocytes that is suppressed by glucocorticoid treatment of monocytes derived from individuals with corticosteroid-sensitive (CS) but not corticosteroid-resistant (CR) asthma. We compared the effects of glucocorticoids on the in vitro generation of other cytokines by monocytes of CS and CR asthmatic individuals. A total of 11 CS and 8 CR asthmatic subjects were studied. Monocytes were cultured overnight in the presence or absence of 5 mug/ml of lipopolysaccharide (LPS) with or without hydrocortisone (HC) or dexamethasone. TNF-alpha, IL-1beta, and GM-CSF were measured by ELISA, mRNA for these cytokines were detected by northern analysis, and NPA was identified by its capacity to enhance ionophore-induced LTB, generation from neutrophils. In the absence of LPS there was no significant difference in the generation of cytokines between monocytes derived from CS and CR individuals. Treatment of monocytes by 10(-6) M HC suppressed NPA generation from CS (72%, p = 0.002) but not CR subjects (10%, p = 0.47). In contrast there was no effect of glucocorticoids on the generation of other cytokines from monocytes of either CS or CR subjects. In the absence of LPS, mRNA for IL-1beta and GM-CSF were not detected by northern analysis, and glucocorticoids had no significant effects on mRNA for TNF-alpha in either group. LPS at 5 mug/ml enhanced cytokine but not NPA generation and markedly increased cytokine mRNA in monocytes of both groups. There was a dose-dependent inhibition of LPS-stimulated NPA generation by glucocorticoids on monocytes of CS but not CR individuals. Glucocorticoid treatment of LPS-stimulated monocytes of both CS and CR subjects led to a dose-dependent inhibition of cytokine generation, with no difference between CS and CR. mRNA for TNF-alpha was not significantly suppressed by glucocorticoid treatment of LPS-stimulated monocytes of either CS or CR subjects; that for IL-1beta and GM-CSF was markedly inhibited by glucocorticoids in both groups. These findings indicate a selective failure of glucocorticoids to inhibit NPA in CR asthmatic individuals.