title: Glucocorticoid receptor-beta up-regulation and steroid resistance induction by IL-17 and IL-23 cytokine stimulation in peripheral mononuclear cells.
abstract: OBJECTIVE
  Most asthmatic patients have well controlled symptoms with regular treatment, but some require much higher doses of inhaled and oral corticosteroids, or in rare cases fail to respond; these patients may present Th-17 cell infiltration and associated cytokines (IL-17A and -F) in the airways, sputum and peripheral blood. Because glucocorticoid receptor-beta (GR-beta) is associated with corticosteroid resistance, we investigated whether Th-17 associated cytokines induce steroid insensitivity in PBMCs via GR-beta up-regulation.
  
  
  METHODS
  GR-alpha, GR-beta, GILZ and IL-6 expression were analyzed in PBMCs stimulated with IL-2/IL-4, IL-17A/IL-17F and IL-23 cytokines by quantitative RT-PCR. Dexamethasone-inhibition of PHA-induced proliferation and Dexamethasone-induced apoptosis were determined by either (3)H-thymidine or CFSE-labelled cells and by Annexin-V staining and flow cytometry.
  
  
  RESULTS
  IL-17 and IL-23 cytokines significantly increased GR-beta expression. IL-2/IL-4 significantly decreased GR-alpha expression without affecting GR-beta. IL17, IL-23 and IL2 + 4 stimulations significantly hampered Dexamethasone-inhibition of proliferation (Dex EC(50) for: IL-17A + F = 251 nM; IL-23 = 435 nM; IL2 + 4 = 950 nM; Medium = 90 nM). IL2 + 4 and IL17A + F but not IL-23, significantly hampered Dexamethasone-induced apoptosis (1400 and 320 nM Dex, respectively). Dexamethasone's trans-activation of GILZ and trans-repression of NF-kB-driven IL-6 expression were both inhibited by IL2 + 4; IL17 + IL23 antagonized Dex trans-repression in PBMC from asthmatics.
  
  
  CONCLUSIONS
  GR-beta up-regulation by IL-17/IL-23 cytokines is associated with induced steroid insensitivity in PBMCs, observed as diminished Dexamethasone's effects on cell proliferation, apoptosis and gene regulation. Steroid resistance induced by IL-2/IL-4 was associated with decreased GR-alpha expression. This study supports the possibility that Th-17 lymphocytes and associated cytokines play a role in the mechanism of steroid hypo-responsiveness in severe asthmatics.
authors.affiliation: Asthma Research Chair and Prince Naif Center for Immunology Research, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Vazquez-Tello
authors.forename: Rabih
authors.initials: R
authors.lastname: Halwani
authors.forename: Qutayba
authors.initials: Q
authors.lastname: Hamid
authors.forename: Saleh
authors.initials: S
authors.lastname: Al-Muhsen
mesh_terms: D000328:Adult; D017209:Apoptosis / Q000187:drug effects; D001249:Asthma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D020381:Interleukin-17 / Q000494:pharmacology*; D053759:Interleukin-23 / Q000494:pharmacology*; D015850:Interleukin-6 / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics
chemical_list: D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D011965:Receptors, Glucocorticoid; C411470:glucocorticoid receptor alpha; C121943:glucocorticoid receptor beta; D003907:Dexamethasone