Molecular mechanisms of stress-induced glucocorticoid resistance in splenic macrophages: A role for p38 MAPK (98.22)

Abstract

Abstract Stress has been shown to increase production of glucocorticoids (GC’s), which suppress the inflammatory response. However, the increased levels of circulating GC’s observed following social disruption stress (SDR) fail to suppress cytokine production or induce apoptosis in splenic CD11b+ cells from WT mice, suggesting that these cells are GC resistant. Moreover, CD11b+ cells from IL-1R1 knockout (KO) mice are not GC resistant following SDR. The results of the present study show that following LPS and corticosterone (LPS/cort) stimulation, CD11b+ cells from WT SDR mice displayed an increase in cytoplasmic p38 phosphorylation (p-p38) when compared to controls. The increase in p-p38 was associated with an increase in nuclear translocation of the GC receptor phosphorylated at Ser234 (GR-pS234), within SDR mice compared to controls. Studies conducted with p38 and JNK inhibitors revealed that a reduction in p38 activity led to an increase in JNK activation and that cytoplasmic GR-pS234 was maintained in SDR and control mice. Furthermore, p-p38 was notably absent in KO macrophages from SDR and control mice stimulated with LPS/cort. These data confirm that SDR enhances GR-pS234 and JNK may facilitate this phosphorylation in the absence of p-p38. These data also support a role for p38 in induction of GC resistance.