A. Trifilieff et al
Stat6-deficiency and lung inflammation
1587
de®cient mice, resistant to bronchoconstriction and have no
IgE, do develop subsequently lung in¯ammation comprising
eosinophil activation and plasma leakage to about 50% of the
levels observed in wild-type mice. These data, together with
previously published work using neutralizing anti-IgE anti-
body (Haile et al., 1999) highlight the important role of IgE for
the development of immediate bronchoconstriction to allergen
in the murine model of lung in¯ammation.
In agreement with recently published studies, sensitized
Stat6-de®cient mice were unable to produce IgE and neither
IL-4 or IL-5 levels could be increased following acute and
chronic allergen challenge (Kuperman et al., 1998; Akimoto et
al., 1998; Tomkinson et al., 1999). The lack of a Th2 response
in Stat6-de®cient mice is consistent with in vitro studies
suggesting the requirement of Stat6 for IL-4-induced Th2 cell
dierentiation and immunoglobulin class switching to IgE
(Shimoda et al., 1996; Kaplan et al., 1996). This is further
supported by in vivo experiments using IL-4-de®cient mice
(Coyle et al., 1995; Brusselle et al., 1995) or neutralizing IL-4
antibody (Coyle et al., 1995) demonstrating the importance of
IL-4 in the commitment of T cells to the Th2 phenotype.
Upon repeated challenge, we have clearly shown that,
despite the lack of IgE and Th2 cytokines, Stat6-de®cient mice
were able to develop a lung eosinophilic in¯ammation of about
20% of that observed in wild-type mice. This strongly suggests
that multiple mechanisms are likely to participate in allergen-
induced lung eosinophilic recruitment depending on the
challenge regimen. Thus, we can suggest that both Stat6-
dependent and -independent mechanisms are involved in the
development of lung eosinophilic in¯ammation following
chronic challenge. Stat6-dependent in¯ammation is likely to
be due to the role of IL-4 in the commitment of T cells to a Th2
phenotype as discussed above. We can only speculate about
the Stat6-independent pathways, but in¯ammation in asthma
and allergic disease is a complex phenomenon involving more
than one signalling pathway. For example, the transcription
factor nuclear factor kB (NF-kB) was shown to play an
important role in the development of airway in¯ammation in
murine model of asthma (Yang et al., 1998) and could
overtake the absence of Stat6 signalling following chronic
stimulation with the antigen.
In conclusion, our results con®rm that Stat6 is an
obligatory transcription factor for the synthesis of IgE
following allergen exposure in vivo. Moreover, Stat6
signalling is also essential for the development of allergic
airway in¯ammation following an acute allergen exposure.
However, in a more chronic situation, the airway in¯am-
matory response seems to be only partially mediated by
Stat6. Since asthmatic patients are exposed chronically to
natural allergens, our results are relevant to the strategies
aimed at targeting the Stat6 pathway for the development of
anti-asthma drugs.
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British Journal of Pharmacology, vol 130 (7)