P-172 - Modulation of FKBP5 Expression by cigarette smoke

Abstract

Cigarette smoke (CS) is one of the most toxic inhaled environmental stressors leading to numerous, preventable, human pathologies. Its deleterious effects on neuro-immunomodulatory systems remain to be documented. We hypothesize that CS activates hypothalamus-pituitary-adrenal axis (HPA axis) releasing glucocorticoids by adrenal cortex. FK506 binding protein 5 (FKBP5), also known as FKBP51 (family of immunophilins) are transcriptionally induced by glucocorticoids and is known to regulate glucocorticoid receptor (GR) responses. Increased expression of FKBP5 was reported to confer ‘glucocorticoid resistance’ by binding to GR and preventing GR-translocation to nucleus. Our focus on FKBP5 was stimulated by data from a genome-wide search for mRNA correlates of (CS)-responsive lung transcriptomes. Studies comparing the lung transcriptomic profile of CS-exposed C57BL6 and AJ mice to air-breathing controls showed elevated levels of FKBP5 mRNA expression in both mouse strains. FKBP5 was also seen to regulate IκBα and p65 nuclear translocation in lung cancer cell lines, suggesting a contributory role of FKBP5 in proinflammatory stimuli of CS. The data suggests that modulation of FKBP5 expression by CS may cause dysregulated GR responses and modulate inflammatory-immune pathways in lungs.