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.
Trivedi
Seema G
SG
Experimental Pathology, St. Bartholomew's and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, United Kingdom.
Newson
Justine
J
Rajakariar
Ravindra
R
Jacques
Thomas S
TS
Hannon
Robert
R
Kanaoka
Yoshihide
Y
Eguchi
Naomi
N
Colville-Nash
Paul
P
Gilroy
Derek W
DW
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