A novel action of IL-13: induction of diminished monocyte glucocorticoid receptor-binding affinity.
We have recently demonstrated that the combination of IL-2 and IL-4 blunts T cell responses to glucocorticoids in steroid resistant (SR) asthma by reducing glucocorticoid receptor (GCR)-binding affinity. Since immune activation appears to be involved in the acquisition of steroid resistance, we sought to identify whether other cytokines could also induce diminished GCR-binding affinity. In the current report, utilizing a [3H]dexamethasone radioligand-binding assay and Scatchard analysis, we found that IL-13, a cytokine with similar actions as IL-4, could induce diminished GCR binding-affinity (GCR Kd = 34.4 +/- 2.3 nM with IL-13 vs Kd = 8.8 +/- 0.7 nM for unstimulated control cells; p < 0.001) in PBMC from normal subjects. In contrast, PBMC incubated with IL-1, IL-3, IL-5, IL-7, IL-8, IL-12, or granulocyte-macrophage-CSF had no effect on GCR-binding affinity; and no additive effect to the decreased GCR-binding affinity was noted when IL-13 was cocultured with IL-2 or IL-4. The cell target of IL-13-induced GCR effects was studied and found to reside in the non-T cell population; specifically, the monocyte fraction. To determine the functional significance of the decreased GCR-binding affinity, monocytes were pretreated with and without IL-1 3 prior to stimulation with LPS and hydrocortisone. IL-13 pretreatment of monocytes significantly diminished (p = 0.005) the suppressive effects of hydrocortisone on LPS-induced IL-6 production. IL-13, by virtue of its ability to induce diminished GCR-binding affinity, may contribute to impaired GC responsiveness during inflammatory illnesses.
Spahn
J D
JD
Ira J. and Jacqueline Neimark Laboratory of Clinical Pharmacology in Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206, USA.
Szefler
S J
SJ
Surs
W
W
Doherty
D E
DE
Nimmagadda
S R
SR
Leung
D Y
DY
D003907:Dexamethasone / Q000378:metabolism*; D006801:Humans; D018793:Interleukin-13 / Q000494:pharmacology* / Q000502:physiology; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000096:biosynthesis* / Q000378:metabolism*
D018793:Interleukin-13; D011965:Receptors, Glucocorticoid; D003907:Dexamethasone