MAPK p38 antagonism as a novel method of inhibiting lymphoid immune suppression in polymicrobial sepsis

Citation
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
Citations number
38
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cell & Developmental Biology
Journal title
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
ISSN journal
0363-6143 → ACNP
Volume
281
Issue
2
Year of publication
2001
Pages
C662 - C669
Database
ISI
SICI code
0363-6143(200108)281:2<C662:MPAAAN>2.0.ZU;2-6
Abstract
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.