Gy. Song et al., IL-4-induced activation of the Stat6 pathway contributes to the suppression of cell-mediated immunity and death in sepsis, SURGERY, 128(2), 2000, pp. 133-138
Background. Although studies have shown that there is a marked depression i
n cell-mediated (T-H1) immunity after the onset of sepsis, the mechanism by
which this occurs remains unknown. In this regard, the T-H2 cytokine IL-4
is known to regulate T-H1 and T-H2 cell responsiveness primarily through th
e activation of the signal transducer and activation of transcription facto
r-6 (Stat6) pathway.
Methods. We hypothesized that IL-4 may contribute to the suppression of cel
l-mediated immunity and to death seen in sepsis and that IL-4 may be acting
through the Stat6 pathway. To determine this, we induced cecal ligation an
d puncture (CLP) or sham-CLP in male BALB/c mice. Mice received 2 mg of mon
oclonal antibody against IL-4 or IgG control ct 12 hours after CLP (ie, at
the onset of immune suppression). Splenic T cells were then isolated 24 hou
rs after CLP and stimulated with monoclonal antibody to CD3. Cytokine relea
se and Stat6 phosphorylation (activation) were determined. In a separate gr
oup of animals, survival was assessed over 10 days.
Results, The results indicate that after CLP, T cells are suppressed in the
ir ability to release the T-H1 cytokines, IL-2 and IFN-gamma. Alternatively
, the release of T-H2 cytokines IL-10 and IL-4 is markedly increased after
CLP. This was associated with an increase in phosphorylated Stat6 protein.
In vivo treatment of mice with monoclonal antibody to IL-4 at 12 hours afte
r CLP restores T-H1 responsiveness while preventing the increase in T-H2 cy
tokine release and Stat6 phosphorylation. Furthermore, neutralization of IL
-4 markedly increased the survival rates in septic animals.
Conclusions. Taken together, these data indicate that the T-H2 cytokine IL-
4 contributes to the suppression of cell-mediated immunity and death associ
ated with polymicrobial sepsis and suggest that IL-4 may be acting through
the Stat6 pathway in septic animals.