Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase (COX)-derived PGH 2 to PGD2 and 15-deoxy⌬ 12-14 PGJ2 (15d-PGJ2). Unlike COX, the role of hPGD2S in host defense is ambiguous. PGD 2 can be either pro-or antiinflammatory depending on disease etiology, whereas the existence of 15d-PGJ 2 and its relevance to pathophysiology remain controversial. Herein, studies on hPGD 2S KO mice reveal that 15d-PGJ2 is synthesized in a self-resolving peritonitis, detected by using liquid chromatography-tandem MS. Together with PGD 2 working on its DP1 receptor, 15d-PGJ 2 controls the balance of pro-vs. antiinflammatory cytokines that regulate leukocyte influx and monocyte-derived macrophage efflux from the inflamed peritoneal cavity to draining lymph nodes leading to resolution. Specifically, inflammation in hPGD 2S KOs is more severe during the onset phase arising from a substantial cytokine imbalance resulting in enhanced polymorphonuclear leukocyte and monocyte trafficking. Moreover, resolution is impaired, characterized by macrophage and surprisingly lymphocyte accumulation. Data from this work place hPGD 2S at the center of controlling the onset and the resolution of acute inflammation where it acts as a crucial checkpoint controller of cytokine/ chemokine synthesis as well as leukocyte influx and efflux. Here, we provide definitive proof that 15d-PGJ 2 is synthesized during mammalian inflammatory responses, and we highlight DP1 receptor activation as a potential antiinflammatory strategy.antiinflammatory ͉ cyclooxygnease ͉ drug development ͉ eicosanoids ͉ innate immunity C yclooxygenase (COX) metabolizes phospholipase A 2 -derived arachidonic acid to prostaglandin (PG)H 2 , which is further metabolized by a series of downsteam synthases to the prostanoids. Indeed, the expression of the particular downstream enzyme and its coupling either to constitutively expressed COX1 or to inducible COX2 will determine the profile and levels of arachidonic metabolites released by cells. Thus, targeting COX will diminish most if not all prostanoids, which, in the case of new-generation COX2 inhibitors, resulted in prostacyclin abatement, enhanced risk of cardiovascular side effects, and the eventual withdrawal of selective COX2 inhibitors from clinical usage. In this event, attention has now shifted to understanding the role of COX downstream synthases in inflammation and the cardiovascular system in the hope of adding more selectivity with fewer side effects.In an attempt to understand the role of COX-related downstream synthase in host defense, we found that the COX2/ hematopoietic PGD 2 synthase pathway resolves both acute innate (1, 2) and adaptive immune responses (3). Hematopoietic PGD 2 synthase (hPGD 2 S) metabolizes COX-derived PGH 2 to PGD 2 (4), which may activate two G protein-coupled receptors, DP1 and DP2. DP1 regulates dendritic cell function (5), and DP2 promotes allergic inflammation (6-8). Although controversial, it is believed that PGD 2 is initially converted to PGJ 2 and 15-deoxy-PGD 2 (15d-PG...

Aspirin and the other NSAIDs have popularized the notion of inhibiting prostaglandins as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are, within the context of inflammation, generally detrimental. However, our fascination with aspirin and the emergence of COX-2 has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epilipoxins, for instance, are produced from aspirin's acetylation of COX-2 and together with Resolvins and COX-2-derived prostaglandins of the D(2) and J(2) series represent an increasingly important family of immunoregulatory lipid mediators with strong implications for disease control and drug discovery.

Hematopoietic prostaglandin D2 synthase (hPGD2S) metabolizes cyclooxygenase-derived prostaglandin (PG) H2 to PGD2, which is dehydrated to cyclopentenone PGs, including 15-deoxy-⌬ 12,14 -PGJ2 (15d-PGJ2). PGD2 acts through two receptors (DP1 and DP2͞CRTH2), whereas 15d-PGJ2 can activate peroxisome proliferator-activated receptors or inhibit a range of proinflammatory signaling pathways, including NF-B. 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, 15d-PGJ2 exerted its suppressive effects through the inhibition of NF-B 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.eicosanoids ͉ inflammation ͉ nonsteroidal antiinflammatory drugs ͉ resolution

Acute inflammation is traditionally described as the influx of polymorphonuclear leukocytes (PMNs) followed by monocyte-derived macrophages, leading to resolution. This is a classic view, and despite subpopulations of lymphocytes possessing innate immune-regulatory properties, seldom is their role in acute inflammation and its resolution discussed. To redress this we show, using lymphocyte-deficient RAG1−/− mice, that peritoneal T/B lymphocytes control PMN trafficking by regulating cytokine synthesis. Once inflammation ensues in normal mice, lymphocytes disappear in response to DP1 receptor activation by prostaglandin D2. However, upon resolution, lymphocytes repopulate the cavity comprising B1, natural killer (NK), γ/δ T, CD4+/CD25+, and B2 cells. Repopulating lymphocytes are dispensable for resolution, as inflammation in RAG1−/− and wild-type mice resolve uniformly. However, repopulating lymphocytes are critical for modulating responses to superinfection. Thus, in chronic granulomatous disease using gp91phox−/− mice, not only is resolution delayed compared with wild-type, but there is a failure of lymphocyte re-appearance predisposing to exaggerated immune responses upon secondary challenge that is rescued by resolution-phase lymphocytes. In conclusion, as lymphocyte repopulation is also evident in human peritonitis, we hereby describe a transition in T/B cells from acute inflammation to resolution, with a central role in modulating the severity of early onset and orchestrating responses to secondary infection.

Sarcoidosis is a chronic relapsing multi-systemic disorder characterized by the development of non-caseating granulomas. Granulomatous tubulo-interstitial nephritis is an uncommon manifestation of this condition. We identified 39 patients with sarcoidosis and renal disease from a single center of whom 17 patients had biopsy-proven tubulo-interstitial nephritis. They were analyzed with respect to demographic and clinical features, including response to corticosteroids and length of follow-up. They all presented with significant renal impairment. At presentation the mean+/-s.d. estimated glomerular filtration rate (eGFR) was 26.8+/-14 ml/min by modification of diet in renal disease (MDRD) equation 7. With treatment there was a significant improvement in renal function with eGFR 49.6+/-5.2 ml/min (P<0.01) at 1 year, and 47.9+/-6.8 ml/min (P<0.05) at the last review. The median follow-up was 84 months (range 6-284 months). Patients with chronic kidney disease (CKD) 3, the mean eGFR was 38.30+/-2.4 ml/min at presentation and 60.2+/-7.4 ml/min at 1 year (P=0.02) and in CKD 4 it improved from 19+/-2 to 38+/-6.6 ml/min at 1 year (P<0.05). After the 1st year, the change in eGFR was +0.8 ml/min/year for CKD 3 and -2 ml/min/year for CKD 4 (P<0.05). Three patients ceased their therapy either due to complications or poor compliance and experienced a worsening of renal function which was then reversed on re-commencing corticosteroids. Corticosteroids are effective in advanced tubulo-interstitial nephritis due to sarcoidosis. Long-term treatment is necessary to preserve renal function and to delay the onset of end-stage renal disease.