Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase-derived prostaglandin (PG) H2 to PGD2, which is dehydrated to cyclopentenone PGs, including 15-deoxy-Δ12,14-PGJ2 (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 hPGD2S 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, 1 5d-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. [ABSTRACT FROM AUTHOR]