Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type hypersensitivity.
Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase-derived prostaglandin (PG) H(2) to PGD(2), which is dehydrated to cyclopentenone PGs, including 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). PGD(2) acts through two receptors (DP1 and DP2/CRTH2), whereas 15d-PGJ(2) can activate peroxisome proliferator-activated receptors or inhibit a range of proinflammatory signaling pathways, including NF-kappaB. Despite eliciting asthmatic and allergic reactions through the generation of PGD(2), it is not known what role hPGD(2)S 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 hPGD(2)S 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-PGJ(2), but not PGD(2), working through either of its receptors. Crucially, 15d-PGJ(2) exerted its suppressive effects through the inhibition of NF-kappaB 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 hPGD(2)S may act as an internal braking signal essential for bringing about the resolution of Th1-driven delayed type hypersensitivity reactions. Consequently, hPGD(2)S-derived cyclopentenone PGs may protect against inflammatory diseases, where T lymphocytes play a pathogenic role, as in rheumatoid arthritis, atopic eczema, and chronic rejection.
Experimental Pathology, St. Bartholomew's and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Seema G
SG
Trivedi
Justine
J
Newson
Ravindra
R
Rajakariar
Thomas S
TS
Jacques
Robert
R
Hannon
Yoshihide
Y
Kanaoka
Naomi
N
Eguchi
Paul
P
Colville-Nash
Derek W
DW
Gilroy
D000818:Animals; D000941:Antigens / Q000276:immunology; D049109:Cell Proliferation; D005121:Extremities / Q000473:pathology; D006410:Hematopoiesis; D006968:Hypersensitivity, Delayed / Q000201:enzymology* / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D007376:Interleukin-2 / Q000096:biosynthesis; D019746:Intramolecular Oxidoreductases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D054834:Lipocalins; D008198:Lymph Nodes / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism; D011453:Prostaglandins / Q000096:biosynthesis; D015398:Signal Transduction
D000941:Antigens; D007376:Interleukin-2; D054834:Lipocalins; D016328:NF-kappa B; D047492:Peroxisome Proliferator-Activated Receptors; D011453:Prostaglandins; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase