Elevated
PGE(2) is a hallmark of most inflammatory lesions. This
lipid mediator can induce the cardinal signs of
inflammation, and the beneficial actions of nonsteroidal anti-inflammatory drugs are attributed to inhibition of
cyclooxygenase (COX)-1 and COX-2,
enzymes essential in the biosynthesis of
PGE(2) from
arachidonic acid. However, both clinical studies and rodent models suggest that, in the asthmatic lung,
PGE(2) acts to restrain the immune response and limit physiological change secondary to
inflammation. To directly address the role of
PGE(2) in the lung, we examined the development of disease in mice lacking microsomal
PGE(2) synthase-1 (mPGES1), which converts COX-1/COX-2-derived
PGH(2) to
PGE(2). We show that mPGES1 determines
PGE(2) levels in the naive lung and is required for increases in
PGE(2) after OVA-induced
allergy. Although loss of either COX-1 or COX-2 increases the disease severity, surprisingly, mPGES1(-/-) mice show reduced
inflammation. However, an increase in serum
IgE is still observed in the mPGES1(-/-) mice, suggesting that loss of
PGE(2) does not impair induction of a Th2 response. Furthermore, mPGES1(-/-) mice expressing a transgenic OVA-specific TCR are also protected, indicating that
PGE(2) acts primarily after challenge with inhaled Ag.
PGE(2) produced by the lung plays the critical role in this response, as loss of lung mPGES1 is sufficient to protect against disease. Together, this supports a model in which mPGES1-dependent
PGE(2) produced by populations of cells native to the lung contributes to the effector phase of some allergic responses.