OBJECTIVES: NF-κB regulated pro-inflammatory cytokines play important roles in coordinating the activities of cells involved in wound healing. Stress has been shown to delay healing and diminish cytokine production, in part, due to elevated serum glucocorticoids. Previous studies showed that treatment of restraint (RST) stressed animals with androstenediol (AED) ameliorated the suppressive function of glucocorticoids, restored pro-inflammatory cytokine gene expression and improved wound closure to approximate that of unstressed controls. These observations serve as the rationale to test the hypothesis that treatment of RST animals with AED will antagonize glucocorticoid-mediated regulation of cytokine production at the transcriptional level (i.e. NF-κB). METHODS: To test this hypothesis, male CD1 outbred mice were subjected to 15-hour cycles of RST beginning 3 days before wounding and continuing for 5 days post wounding. Control animals were food and water deprived (FWD) during the same time period. Animals were wounded with a 3.5 mm biopsy punch, and healing was assessed daily by photoplanimetry. In addition, at 3, 6, 12, and 24 hours and 3 and 5 days post wounding, a 6.0 mm punch was used to collect the wound and surrounding tissue. Total RNA was collected, cDNA was synthesized and real time PCR was used to quantify IκBα RNA as a surrogate marker of NF-κB activation. RESULTS: RST delayed wound closure compared to controls (P<0.001), and decreased IκBα expression 12 hours after wounding (P=0.021). In contrast, treatment with AED restored wound closure to that of the controls. Furthermore, treatment with AED augmented NF-κB activity as illustrated by elevated IκBα gene expression as early as 24 hours after wounding (P<0.001). CONCLUSIONS: These data show that the inhibitory effects of stress on wound healing and inflammatory cytokine production, which are prevented by AED, may be mediated through an NF-κB-dependent mechanism. Supported by AG16321 and DE14304.

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