Cyclooxygenase-2 Regulates Th17 Cell Differentiation during Allergic Lung Inflammation

Laboratories of Respiratory Biology
American Journal of Respiratory and Critical Care Medicine (Impact Factor: 13). 04/2011; 184(1):37-49. DOI: 10.1164/rccm.201010-1637OC
Source: PubMed


Th17 cells comprise a distinct lineage of proinflammatory T helper cells that are major contributors to allergic responses. It is unknown whether cyclooxygenase (COX)-derived eicosanoids regulate Th17 cells during allergic lung inflammation.
To determine the role of COX metabolites in regulating Th17 cell differentiation and function during allergic lung inflammation.
COX-1(-/-), COX-2(-/-), and wild-type mice were studied in an in vivo model of ovalbumin-induced allergic inflammation and an in vitro model of Th17 differentiation using flow cytometry, cytokine assays, confocal microscopy, real-time polymerase chain reaction, and immunoblotting. In addition, the role of specific eicosanoids and their receptors was examined using synthetic prostaglandins (PGs), selective inhibitors, and siRNA knockdown.
Th17 cell differentiation in lung, lymph nodes, and bronchoalveolar lavage fluid was significantly lower in COX-2(-/-) mice after ovalbumin sensitization and exposure in vivo. In vitro studies revealed significantly impaired Th17 cell differentiation of COX-2(-/-) naive CD4(+) T cells with decreased Stat3 phosphorylation and RORγt expression. Synthetic PGF(2α) and PGI(2) enhanced Th17 cell differentiation of COX-2(-/-) CD4(+) T cells in vitro. The selective COX-2 inhibitor, NS-398, and PGF(2α) receptor and PGI(2) receptor siRNA knockdown significantly decreased Th17 cell differentiation in vitro. Administration of synthetic PGs restored accumulation of Th17 cells in lungs of allergic COX-2(-/-) mice in vivo.
COX-2 is a critical regulator of Th17 cell differentiation during allergic lung inflammation via autocrine signaling of PGI(2) and PGF(2α) through their respective cell surface receptors.

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    • "Cyclooxygenases (COX) generate a variety of prostaglandins (PGs), which have been implicated in a number of physiological events, including the progression of inflammation and immunomodulation, and the transmission of pain (Kamei et al., 2004). COX-2, the inducible enzyme induced by inflammatory stimuli such as cytokines , generates PGs that contribute to the pain and swelling of inflammation (Li et al., 2011). Although COX-2 is normally expressed at very low levels, it is rapidly induced by a variety of stimuli, such as cytokines , growth factors, hormones, and carcinogens, and it is believed to be responsible for producing the PGs associated with the mediation of inflammation (Ghoshal et al., 2011; Leiro et al., 2004). "
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    • "Early work exploring the involvement on PG on T cell locomotion considered the involvement of PGF2α but this was not supported by the resulting data (93). However, a recent report on allergic lung inflammation presents evidence for the contribution of PGF2α in Th17 cell differentiation, an autocrine effect mediated through cell surface FP receptors (123). "
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    • "This prostaglandin can be synthesized through a number of different pathways (Basu, 2010), but there appears to be no evidence for any PGF2α synthesis in T cells. Evidence for a role of PGF2α signaling in T cells is also very limited, although a recent study demonstrated a role for this prostaglandin in promoting Th17 differentiation during allergic lung inflammation (Li et al., 2011). In this study, the authors propose that PGF2α together with PGI2 promotes differentiation of Th17 cells – proinflammatory cells and major contributors in allergic responses – from naïve CD4+ cells by signaling through their respective receptors in an autocrine fashion. "
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