The role of cyclic adenosine monophosphate in the suppression of cellular immunity after thermal injury
A. F. Horgan, D. S. O'Riordain, D. H. Chin, J. A. Mannick and M. L. Rodrick
Department of Surgery, Harvard Medical School, Brigham and Women's Hospital, Boston, Mass.
BACKGROUND AND OBJECTIVE: Cyclic adenosine monophosphate (cAMP) is an
intracellular second messenger that is known to convey inhibitory signals
for T-cell proliferation and function. We investigated the association
between this molecule and the profound immunosuppression that accompanies
thermal injury. DESIGN: Mice were randomized into two groups: one group was
subjected to a 20% full-thickness scald burn; the second to a sham burn
(control). The mice were killed on days 4, 7, or 10 after the burn injury
and splenocytes were pooled and cultured for 15 minutes in the presence or
absence of prostaglandin E2 (PGE2). RESULTS: Levels of cAMP in splenocytes
were significantly elevated on day 7 after burn in the burn group compared
with the sham controls (P < .05, Wilcoxon Rank Sum Test). Incubation of
splenocytes with PGE2 resulted in significantly greater levels of
intracellular cAMP in cells from the burn group compared with controls on
days 4, 7, and 10. Incubation of normal splenocytes with dibutyryl cAMP in
the presence of concanavalin A significantly decreased cell proliferation
and the production of interleukin-2. The decrease in interleukin-2
production was evident at the level of messenger RNA expression.
Stimulation of splenocytes with a combination of phorbol ester and calcium
ionophore, bypassing all membrane-associated events prior to protein kinase
C activation, reversed the inhibitory effects of dibutyryl cAMP. Incubation
of splenocytes from burned animals with H-8, a selective inhibitor of
cAMP-dependent protein kinases, restored the proliferative response to that
of sham controls on days 4, 7, and 10 after thermal injury. CONCLUSIONS:
These data indicate that elevated levels of intracellular cAMP, combined
with an increased production of cAMP in response to circulating PGE2, may
play a fundamental role in suppression of the immune response following
thermal injury and that cAMP exerts its immunomodulatory effects prior to
protein kinase C activation.
