PGE2 and PGI2 are the predominant prostanoids associated with inflammation. Both markedly enhance edema formation and leukocyte infiltration by promoting blood flow in the inflamed region. PGE2 and PGI2, through activation of EP2 and IP, respectively, increase vascular permeability and leukocyte infiltration. Through its action as a platelet agonist, TXA2 can also increase platelet-leukocyte interactions. Although probably not made by lymphocytes, prostaglandins may potently regulate lymphocyte function. PGE2 and TXA2 may play a role in T-lymphocyte development by regulating apoptosis of immature thymocytes. PGI2 contributes to immune suppression by interfering with dendritic cell maturation and antigen uptake for presentation to immune cells. PGE2 suppresses the immunologic response by inhibiting differentiation of B lymphocytes into antibody-secreting plasma cells, thus depressing the humoral antibody response. It also inhibits cytotoxic T-cell function, mitogen-stimulated proliferation of T lymphocytes, and maturation and function of Th1 lymphocytes. PGE2 can modify myeloid cell differentiation, promoting type 2 immune-suppressive macrophage and myeloid suppressor cell phenotypes. These effects likely contribute to immune escape in tumors where infiltrating myeloid-derived cells predominantly display type 2 phenotypes. PGD2, a major product of mast cells, is a potent chemoattractant for eosinophils in which it also induces degranulation and leukotriene biosynthesis. PGD2 also induces chemotaxis and migration of Th2 lymphocytes, mainly via activation of DP2, although a role for DP1 has also been established. It remains unclear how these two receptors coordinate the actions of PGD2 in inflammation and immunity. A degradation product of PGD2, 15d-PGJ2, at concentrations actually formed in vivo, may also activate eosinophils via the DP2 (CRTh2) receptor.
G. Bone Metabolism
Prostaglandins are abundant in skeletal tissue and are produced by osteoblasts and adjacent hematopoietic cells. The major effect of prostaglandins (especially PGE2, acting on EP4) in vivo is to increase bone turnover, ie, stimulation of bone resorption and formation.
EP4 receptor deletion in mice results in an imbalance between bone resorption and formation, leading to a negative balance of bone mass and density in older animals. Prostaglandins may mediate the effects of mechanical forces on bones and changes in bone during inflammation. EP4-receptor deletion and inhibition of prostaglandin biosynthesis have both been associated with impaired fracture healing in animal models. COX inhibitors can also slow skeletal muscle healing by interfering with prostaglandin effects on myocyte proliferation, differentiation, and fibrosis in response to injury. Prostaglandins may contribute to the bone loss that occurs at menopause; it has been speculated that NSAIDs may be of therapeutic value in osteoporosis and bone loss prevention in older women. However, controlled evaluation of such therapeutic interventions has not been carried out. NSAIDs, especially those specific for inhibition of COX-2, delay bone healing in experimental models of fracture.
H. Eye
PGE, PGF, and PGD derivatives lower intraocular pressure. The mechanism of this action is unclear but probably involves increased outflow of aqueous humor from the anterior chamber via the uveoscleral pathway (see Clinical Pharmacology of Eicosanoids).
I. Cancer