T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids.
Glucocorticoids (GC) are steroid hormones that modulate T cell functions and restrain their hyperresponsiveness following stimulation. Naive T lymphocytes are sensitive to GC but become more resistant when they are activated. A balance between activation and inhibition signals is important for a targeted and effective T cell response. Thermal injury is characterized by an immune dysfunction and hyperactive T cells visible at day 10 postburn. In this study, our objective was to evaluate T cell sensitivity to GC following thermal injury and to identify mechanisms that could modulate their sensitivity. One mechanism that we hypothesized was increased p38 mitogen-activated protein kinase (MAPK) activity that could lead to GC resistance. Male C57BL/6 mice underwent a full-thickness 20% total body surface area. At 10 days postinjury, splenic T cells were isolated. Glucocorticoid receptor (GR) expression was higher in T cells from burn-injured mice. Interestingly, these cells were also less sensitive to GC-induced apoptosis prior to and poststimulation. Furthermore, anti-CD3-activated T cells from burn-injured mice showed increased proliferation and CD25 expression, which resisted corticosterone's (CORT) suppressive effect. Anti-CD3-activated CD4(+)CD44(+) memory cells from burn-injured mice expressed the highest level of CD25 and were resistant to CORT. Increased phosphorylation of p38 MAPK was also noted in activated T cells from burn-injured mice. Pharmacological inhibition of p38 MAPK decreased cell proliferation and normalized interferon-gamma (IFNgamma) production. In conclusion, we demonstrate that a unique event like burn injury induces a loss of sensitivity to GC in splenic T cells and have identified p38 MAPK as a key modulator for this resistance.
INRS, Institut Armand-Frappier, 531 boulevard des Prairies, Laval, Quebec, Canada.
Michele
M
D'Elia
Julie
J
Patenaude
Charles
C
Dupras
Jacques
J
Bernier
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D002056:Burns / Q000473:pathology*; D017252:CD3 Complex / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D049109:Cell Proliferation; D004351:Drug Resistance; D005452:Fluoresceins; D005938:Glucocorticoids / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D008297:Male; D051379:Mice; D010641:Phenotype; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013388:Succinimides; D013601:T-Lymphocytes / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D017252:CD3 Complex; D005452:Fluoresceins; D005938:Glucocorticoids; D053645:Interleukin-2 Receptor alpha Subunit; D011965:Receptors, Glucocorticoid; D013388:Succinimides; D007371:Interferon-gamma; D048051:p38 Mitogen-Activated Protein Kinases