Disruption of poly (ADP-ribose) polymerase (PARP) protects against stress-evoked immunocompromise.
BACKGROUND
Chronic stress, mediated by adrenal hormones, is a major risk factor in the progression and outcome of human disease. While the secretion of adrenal hormones is known to be the primary endocrine mediator of stress-induced immunocompromise, the molecular mechanisms underlying the immunocompromise remain unspecified. Overproduction of the nuclear enzyme, poly (ADP-ribose) polymerase (PARP) has been implicated in the molecular pathway that leads to cell death by energy depletion following stress.


METHODS
Wild-type (WT) mice and mice with targeted disruption of the gene encoding PARP-1 (PARP-1 -/-) were subjected to 2 wk daily cold-water swim; splenocyte proliferation, anti-KLH IgG, and serum corticosterone concentrations were assessed. Additional mice of each genotype received daily i.p. injections of dexamethasone (DEX) (0.75 mg/kg) for 2 wk, and splenocyte proliferation and anti-KLH IgG were assessed.


RESULTS
Splenocyte proliferation and specific antibody concentrations of stressed WT mice were reduced by ~20% of their pre-stress levels. In contrast, PARP-1 -/- mice maintained normal cell-mediated and humoral immune function following enforced cold-water swim stress. PARP-1 -/- mice also failed to compromise immune function following DEX treatment, whereas WT mice displayed significant reductions of immune function following this treatment.


CONCLUSIONS
These results provide support for the involvement of PARP activation in immunological damage following physical stress. These results suggest that glucocorticoid-induced immunosuppression may require the activation of PARP in order for apoptosis of immune cells to take place. Taken together, these results suggest that therapies designed to inhibit PARP may prove valuable in the treatment of stress-related diseases.
Drazen
D L
DL
Department of Psychology, The Johns Hopkins University, Baltimore, MD, USA.
Bilu
D
D
Edwards
N
N
Nelson
R J
RJ
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology; D006433:Hemocyanins / Q000276:immunology; D007109:Immunity / Q000235:genetics* / Q000502:physiology; D007165:Immunosuppression Therapy; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics* / Q000502:physiology; D013312:Stress, Physiological / Q000201:enzymology / Q000235:genetics* / Q000276:immunology*; D013550:Swimming
D000893:Anti-Inflammatory Agents; D003907:Dexamethasone; D006433:Hemocyanins; D011065:Poly(ADP-ribose) Polymerases; C032808:keyhole-limpet hemocyanin