title: Dysregulation of interleukin 4, interleukin 5, and interferon gamma gene expression in steroid-resistant asthma.
abstract: In steroid-resistant (SR) asthma, there is a lack of clinical responsiveness to oral prednisone. Previous studies indicate that this may be explained by the effect of the combination of interleukin 2 (IL-2) and IL-4 on glucocorticoid receptor binding affinity. By contrast, steroid-sensitive (SS) asthmatics respond well to glucocorticoids, and this is accompanied by a decrease in the numbers of bronchoalveolar lavage (BAL) messenger RNA+ (mRNA+) cells expressing IL-4 and IL-5, and an increase in interferon gamma (IFN-gamma) transcripts. In the present study, we hypothesized that SR asthma is associated with alterations in T helper types 1/2 (Th2/Th1)-type cytokine gene expression. BAL was performed in six SR asthmatics and six SS asthmatics, before and after a 1-wk course of 40 mg daily prednisone. mRNA+ cells for IL-2, IL-4, IL-5, and IFN-gamma was measured by in situ hybridization using 35S-labeled RNA probes. Before prednisone therapy, there were significantly greater numbers of BAL cells (per 1,000) expressing IL-2 mRNA (p < 0.01) and IL-4 mRNA (p < 0.05) in SR asthmatics as compared with SS asthmatics, but no differences between the two groups in the numbers of BAL cells expressing IFN-gamma or IL-5 mRNA expression were observed. After a 1-wk course of prednisone, IL-2 expression was not altered in either group. However, SS asthmatics had a significant decrease in the numbers of BAL cells expressing mRNA for IL-4 (p < 0.01) and IL-5 (p < 0.001), and a rise in the numbers of IFN-gamma mRNA+ cells (p < 0.01). In contrast, after prednisone treatment, SR asthmatics had no significant change in either the number of BAL cells expressing mRNA for IL-4 or IL-5. Of note, there was an unexpected decrease in the numbers of IFN-gamma mRNA+ cells (p = 0.05). Our current findings indicate that SR asthma is associated with a dysregulation of the expression of the genes encoding for Th2/Th1 cytokines in airway cells and is compatible with the concept that a combination of IL-2 and IL-4 induce glucocorticoid (GR) binding affinity and T cell responsiveness to glucocorticoids.
authors: Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
authors: D Y
authors: DY
authors: Leung
authors: R J
authors: RJ
authors: Martin
authors: S J
authors: SJ
authors: Szefler
authors: E R
authors: ER
authors: Sher
authors: S
authors: S
authors: Ying
authors: A B
authors: AB
authors: Kay
authors: Q
authors: Q
authors: Hamid
mesh_terms: D000328:Adult; D001249:Asthma / Q000473:pathology / Q000503:physiopathology*; D001992:Bronchoalveolar Lavage Fluid; D004351:Drug Resistance; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D017403:In Situ Hybridization; D007371:Interferon-gamma / Q000502:physiology*; D015847:Interleukin-4 / Q000502:physiology*; D015848:Interleukin-5 / Q000502:physiology*; D008297:Male; D011241:Prednisone / Q000008:administration & dosage*
chemical_list: D015848:Interleukin-5; D015847:Interleukin-4; D007371:Interferon-gamma; D011241:Prednisone