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Abstract

The aim of this study was to define the immunoregulatory role of prostaglandins in a mouse model of Strongyloides venezuelensis infection. Strongyloides venezuelensis induced an increase of eosinophils and mononuclear cells in the blood, peritoneal cavity fluid, and bronchoalveolar lavage fluid. Treatment with the dual cyclooxygenase (COX-1/-2) inhibitors indomethacin and ibuprofen, and the COX-2-selective inhibitor celecoxib partially blocked these cellular responses and was associated with enhanced numbers of infective larvae in the lung and adult worms in the duodenum. However, the drugs did not interfere with worm fertility. Cyclooxygenase inhibitors also inhibited the production of the T-helper type 2 (Th2) mediators IL-5, IgG1, and IgE, while indomethacin alone also inhibited IL-4, IL-10, and IgG2a. Cyclooxygenase inhibitors tended to enhance the Th1 mediators IL-12 and IFN-gamma. This shift away from Th2 immunity in cyclooxygenase inhibitor-treated mice correlated with reduced prostaglandin E(2) (PGE(2)) production in infected duodenal tissue. As PGE(2) is a well-characterized driver of Th2 immunity, we speculate that reduced production of this lipid might be involved in the shift toward a Th1 phenotype, favoring parasitism by S. venezuelensis. These findings provide new evidence that cyclooxygenase-derived lipids play a role in regulating host defenses against Strongyloides, and support the exploration of eicosanoid signaling for identifying novel preventive and therapeutic modalities against these infections.

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Cyclooxygenases 1 and 2.

J R Vane, Y Bakhle, R. M. Botting (1998)

Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.

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Prostaglandins in health and disease: an overview.

Justin Miller (2006)

Prostaglandins are a group of biologically active compounds that play major roles in human physiology in both health and disease. They function in many different ways and in all major organs. This article reviews the basic physiology of prostaglandins and their application to specific effects on these systems in normal and abnormal clinical states. The critical therapeutic implications of the use of nonsteroidal antiinflammatory drugs in altering organ homeostasis are also examined. References were taken from Medline, Embase, and Index Medicus from 1966 to September 2005. A search was done with keywords, including prostaglandins, nonsteroidal antiinflammatory drugs, inflammation, arachidonic acid, Cox-1 (cyclooxygenase-1), and Cox-2 (cyclooxygenase-2). There was a close correlation and predictability between basic prostaglandin physiology and the anticipated effects of these compounds on the heart, lungs, kidneys, gastrointestinal tract, bones and joints, brain, and male and female reproductive systems. These effects are organ and tissue specific. Despite these findings, unexplained and sometimes paradoxical physiologic responses were identified. A prime example of this is the role of prostaglandins in bone metabolism demonstrating both stimulatory and inhibitory effects. In addition all NSAIDs have the potential to impair the normal physiologic effects of prostaglandins depending primarily on the specific organ and the clinical setting. Prostaglandins are regulatory compounds that play important roles in many physiologic processes in the human body. An understanding of the basic science of prostaglandins is valuable in anticipating the organ-specific biologic effects of these unique compounds in health and disease. However, at selected sites and under different physiologic conditions, unexplained and sometimes paradoxical effects are generated. Impairment of their regulatory functions can lead to significant short- or long-term organ dysfunction.

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Pivotal roles of the parasite PGD2 synthase and of the host D prostanoid receptor 1 in schistosome immune evasion.

Christelle Faveeuw, E Pinzar, André Capron … (2003)

Prostaglandins (PG) are important modulators of immune and inflammatory responses. We recently demonstrated that the production of PGD(2) by the helminthic parasite Schistosoma mansoni inhibits the migration of epidermal Langerhans cells (LC) to the draining lymph nodes (DLN). Here, we identify the responsible parasite enzyme as being a 28-kDa glutathione-S-transferase (termed Sm28GST). Intradermal injection of Sm28GST in wild-type (WT), but not in D prostanoid receptor (DP) 1-deficient mice abrogates the departure of LC from the epidermis after TNF-alpha or FITC treatment. During infection, DP1 deficiency restores LC migration, but does not enhance the rate of T cell proliferation in the skin DLN. However, relative to WT mice, DLN cells from DP1-deficient infected mice produce dramatically less IFN-gamma and IL-10, but equal amount of IL-4. Interestingly, infected DP1-deficient mice develop a more Th2-biased humoral immune response, a significantly reduced parasitemia and a decreased egg-induced inflammatory response in the liver and intestines. Taken together, we propose that DP1 activation by the Sm28GST-derived PGD(2) could represent a strategy for the schistosome to evade host immune defenses. We also suggest that DP1 is important in the Th1/Th2 balance of the immune response and in inflammatory reactions during infection.