Details

Autor(en) / Beteiligte

• Trivedi, Seema G.
• Newson, Justine
• Rajakariar, Ravindra
• Jacques, Thomas S.
• Hannon, Robert
• Kanaoka, Yoshihide
• Eguchi, Naomi
• Colville-Nash, Paul
• Gilroy, Derek W.

Titel

Essential Role for Hematopoietic Prostaglandin D2 Synthase in the Control of Delayed Type Hypersensitivity

Ist Teil von

• Proceedings of the National Academy of Sciences - PNAS, 2006-03, Vol.103 (13), p.5179-5184

Ort / Verlag

United States: National Academy of Sciences

Erscheinungsjahr

2006

Quelle

MEDLINE

Beschreibungen/Notizen

• Hematopoietic prostaglandin D₂ synthase (hPGD₂S) metabolizes cyclooxygenase-derived prostaglandin (PG) H₂ to PGD₂, which is dehydrated to cyclopentenone PGs, including$15-deoxy-\Delta^{12,14}-PGJ_{2}$(15d-PGJ₂). PGD₂ acts through two receptors (DP1 and DP2/CRTH2), whereas 15d-PGJ₂ can activate peroxisome proliferator-activated receptors or inhibit a range of proinflammatory signaling pathways, including NF-κB. Despite eliciting asthmatic and allergic reactions through the generation of PGD₂, it is not known what role hPGD₂S plays in T helper (Th)1-driven adaptive immunity. To investigate this question, the severity and duration of a delayed type hypersensitivity reaction was examined in hPGD₂S knockout and transgenic mice. Compared with their respective controls, knockouts displayed a more severe inflammatory response that failed to resolve, characterized histologically as persistent acute inflammation, whereas transgenic mice had little detectable inflammation. Lymphocytes isolated from inguinal lymph nodes of$hPGD_{2}S^{-/-}$animals showed hyperproliferation and increased IL-2 synthesis effects that were rescued by 15d-PGJ₂, but not PGD₂, working through either of its receptors. Crucially, 15d-PGJ₂ exerted its suppressive effects through the inhibition of NF-κB activation and not through peroxisome proliferator-activated receptor signaling. In contrast, lymph node cultures from transgenics proliferated more slowly and synthesized significantly less IL-2 than controls. Therefore, contrary to its role in driving Th2-like responses, this report shows that hPGD₂S may act as an internal braking signal essential for bringing about the resolution of Th1-driven delayed type hypersensitivity reactions. Consequently, hPGD₂S-derived cyclopentenone PGs may protect against inflammatory diseases, where T lymphocytes play a pathogenic role, as in rheumatoid arthritis, atopic eczema, and chronic rejection.