Gy. Song et al., MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis, AM J P-CELL, 281(2), 2001, pp. C662-C669
Although studies indicate that a shift from a Th1 to a Th2 response contrib
utes to a marked suppression of cell-mediated immunity during sepsis, the m
echanism by which this occurs remains unknown. Given that the mitogen-activ
ated protein kinase (MAPK) p38 plays a critical role in the activation and
function of immune cells, the aim of this study was to determine the contri
bution of MAPK p38 activation to the immune dysfunction seen in polymicrobi
al sepsis. To study this, polymicrobial sepsis was induced in C3H/HeN male
mice by cecal ligation and puncture (CLP). Splenic lymphocytes and purified
T cells were harvested 24 h post-CLP, pretreated with the specific MAPK p3
8 inhibitor SB-203580, and then stimulated with a monoclonal antibody again
st the T cell marker CD3. The results indicate that interleukin (IL)-2 rele
ase is markedly depressed while the release of the immunosuppressive mediat
or, IL-10, as well as mRNA levels of IL-10 and IL-4, are augmented after CL
P. Inhibition of MAPK p38 suppressed in vitro IL-10 levels as well as IL-10
and IL-4 gene expression while restoring the release of IL-2. To determine
whether these in vitro findings could be translated to an in vivo setting,
mice were given 100 mg of SB-203580/kg body wt or saline vehicle (intraper
itoneal) at 12 h post-CLP. Examination of ex vivo lymphocyte responsiveness
indicated that, as with the in vitro finding, septic mouse Th1 responsiven
ess was restored. In light of our recent finding that delayed in vivo SB-20
3580 treatment also improved survival after CLP, we believe that these resu
lts not only illustrate the role of MAPK p38 in the induction of immunosupp
ressive agents in sepsis but demonstrate that SB-203580 administration afte
r the initial proinflammatory state of sepsis significantly prevents the mo
rbidity from sepsis.