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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.

Pubmed ID: 16547141


  • Trivedi SG
  • Newson J
  • Rajakariar R
  • Jacques TS
  • Hannon R
  • Kanaoka Y
  • Eguchi N
  • Colville-Nash P
  • Gilroy DW


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

March 28, 2006

Associated Grants

  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Animals
  • Antigens
  • Cell Proliferation
  • Extremities
  • Hematopoiesis
  • Hypersensitivity, Delayed
  • Inflammation
  • Interleukin-2
  • Intramolecular Oxidoreductases
  • Lipocalins
  • Lymph Nodes
  • Mice
  • Mice, Knockout
  • NF-kappa B
  • Peroxisome Proliferator-Activated Receptors
  • Prostaglandins
  • Signal Transduction