Heme oxygenase-1 (HO-1) is an inducible rate-limiting enzyme which catalyzes group heme into carbon monoxide, iron and bilirubin. In the recent years, HO-1 expression has been reported as an important protective endogenous mechanism against physical, chemical and biological stress. In this regard, induction of this enzyme has shown beneficial effects in several pathologic conditions, such as inflammatory processes, atherosclerosis, carcinogenesis, ischemia-reperfusion systems or degenerative diseases. Complex intracellular signalling cascades mediate the expression of HO-1 in response to external stimuli, Transcription factors, as nuclear factor E2 – related factor-2, activator protein-1, and nuclear factor-kappa B, and some of their upstream kinases, mitogen-activated protein kinases, phosphatidylinositol 3-kinase, or protein kinases A, C are responsible of the HO-1 gene expression. The purpose of this article is to review the increasing number of natural and synthetic molecules reported to induce HO-1 as additive mechanism responsible for their therapeutic effects; experimental and pathological conditions as well as possible signalling mechanism involved in HO-1 expression by this compounds are described. Controlled upregulation of this enzyme, or its catalytic activity, has shown antioxidant, anti-proliferative, anti-apoptotic and anti-inflammatory properties. For this reason, pharmacologic modulation of HO- 1 system may represent an effective and cooperative strategy to intervene in several pathologic conditions.

Objective: Prostaglandin D₂ (PGD₂) may exert proinflammatory or antiinflammatory effects in different biologic systems. Although this prostanoid and the enzymes responsible for its synthesis are up‐regulated by interleukin‐1β (IL‐1β) in human chondrocytes in vitro, the role of PGD₂ in arthritis remains unclear. This study was undertaken to investigate the role of PGD₂ in the inflammatory response and in joint destruction during the development of collagen‐induced arthritis (CIA) in mice.Methods: PGD₂ and cytokine levels in mice with CIA were determined by enzyme‐linked immunosorbent assay. Expression of hematopoietic PGD synthase (h‐PGDS), lipocalin‐type PGD synthase (l‐PGDS), and DP1 and DP2 receptors was analyzed by immunohistochemical methods. PGE₂ levels were determined by radioimmunoassay.Results: The arthritic process up‐regulated the expression of h‐PGDS, l‐PGDS, DP1, and DP2 in articular tissue. PGD₂ was produced in the joint during the early phase of arthritis, and serum PGD₂ levels increased progressively throughout the arthritic process, reaching a maximum during the late stages of CIA. Treatment of arthritic mice with the DP1 antagonist MK0524 soon after the onset of disease increased the incidence and severity of CIA as well as the local levels of IL‐1β, CXCL‐1, and PGE₂, whereas IL‐10 levels were reduced. The administration of the DP2 antagonist CAY10595 did not modify the severity of arthritis. The injection of PGD₂ into the paw, as well as the administration of the DP1 agonist BW245C, significantly lowered the incidence of CIA, the inflammatory response, and joint damage.Conclusion: Our findings indicate that PGD₂ is produced in articular tissue during the development of CIA and plays an antiinflammatory role, acting through the DP1 receptor.