Decreased steroid responsiveness at night in nocturnal asthma. Is the macrophage responsible?
As peripheral blood mononuclear cells from patients with nocturnal asthma (NA) exhibit reduced steroid responsiveness at 4:00 A.M. as compared with 4:00 P.M., we hypothesized that NA is associated with increased nocturnal airway cell expression of GRbeta, an endogenous inhibitor of steroid action. Ten subjects with NA and seven subjects with nonnocturnal asthma (NNA) underwent bronchoscopy with bronchoalveolar lavage (BAL) at 4:00 P.M. and 4:00 A.M. BAL lymphocytes and macrophages were incubated with dexamethasone (DEX) at 10(-5) to 10(-8) M. DEX suppressed proliferation of BAL lymphocytes similarly at 4:00 P.M. and 4:00 A.M. in both groups. However, BAL macrophages from NA exhibited less suppression of IL-8 and TNF-alpha production by DEX at 4:00 A.M. as compared with 4:00 P.M. (p = 0.0001), whereas in the NNA group DEX suppressed IL-8 and TNF-alpha production equally at both time points. GRbeta expression was increased at night only in NA, primarily due to significantly increased expression by BAL macrophages (p = 0.008). IL-13 mRNA expression was increased at night, but only in the NA group and addition of neutralizing antibodies to IL-13 reduced GRbeta expression by BAL macrophages. We conclude that the airway macrophage may be the airway inflammatory cell driving the reduction in steroid responsiveness at night in NA, and this function is modulated by IL-13.
Kraft
M
M
Departments of Medicine and Pediatrics, National Jewish Medical and Research Center, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA. kraftm@njc.org
Hamid
Q
Q
Chrousos
G P
GP
Martin
R J
RJ
Leung
D Y
DY
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002940:Circadian Rhythm; D003907:Dexamethasone / Q000494:pharmacology*; D005260:Female; D006801:Humans; D018793:Interleukin-13 / Q000235:genetics / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D016018:Least-Squares Analysis; D008214:Lymphocytes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D018793:Interleukin-13; D016209:Interleukin-8; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D014409:Tumor Necrosis Factor-alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone