Influence of heme oxygenase 1 modulation on the progression of murine collagen‐induced arthritis

Abstract

Objective. Heme oxygenase 1 (HO-1) can be induced by inflammatory mediators as an adaptive response. The objective of the present study was to determine the consequences of HO-1 modulation in the murine collagen-induced arthritis (CIA) model.Methods. DBA/1J mice were treated with an inhibitor of HO-1, tin protoporphyrin IX (SnPP), or with an inducer of HO-1, cobalt protoporphyrin IX (CoPP), from day 22 to day 29 after CIA induction. The clinical evolution of disease was monitored visually. At the end of the experiment, joints were examined for histopathologic changes. Cytokine levels in paws were measured by enzyme-linked immunosorbent assay. Levels of HO-1, cyclooxygenase 2 (COX-2), and prostaglandin E 2 (PGE 2 ) were determined. Effects of treatments on the early phase of disease and after prophylactic administration were also assessed.Results. CoPP strongly induced HO-1, resulting in the inhibition of cartilage erosion accompanied by extensive fibrosis in the joint. Levels of tumor necrosis factor ␣ (TNF␣), interleukin-2 (IL-2), and IL-10 were inhibited by CoPP, whereas levels of vascular endothelial growth factor were increased. Treatment with SnPP significantly reduced the severity of CIA, with inhibition of joint inflammation and cartilage destruction. The levels of PGE 2 , IL-1␤, and TNF␣ were also significantly reduced by SnPP treatment, which did not modify COX-2 protein expression. SnPP was more effective than CoPP in preventing the development of CIA (prophylactic administration).Conclusion. HO-1 is induced during CIA. Although overexpression of this protein causes some beneficial effects, strategies aimed at HO-1 overexpression cannot slow the progression of the chronic inflammatory disease, whereas treatment with SnPP, which inhibits HO-1, exerts prophylactic and therapeutic effects.

Heme Oxygenase-1-Mediated CD4+CD25high Regulatory T Cells Suppress Allergic Airway Inflammation

“…A wide variety of agents, including heavy metals, cytokines, hormones, endotoxin, and heat shock, have been identified as strong inducers of HO-1 expression. The induction of endogenous HO-1 or exogenous administration of HO-1 via inducers and transgene provides protection against tissue injury and oxidative stress in many in vivo and in vitro Table II models (14,15). Pretreatment with hemin can induce HO-1 expression, and increase HO-1 activity before OVA sensitization and challenge, which persists for 72 h in our studies.…”

Inhibition of Heme Oxygenase-1 Interferes with the Transforming Activity of the Kaposi Sarcoma Herpesvirusencoded G Protein-coupled Receptor

“…The capacity of HO-1 to induce VEGF expression and cell growth in vivo has also been observed in rat placenta, where transduction with adenoviral human HO-1 resulted in increased expression of vascular endothelial growth factor and pup size, whereas inhibition of the enzyme by metalloporphyrins decreased fetal growth (67). Noteworthy, SnPP has been extensively used in vivo to treat several pathologies including murine collagen-induced arthritis (68) and hyperbilirubinemia in rats, monkeys, and humans (69 -71). A recent clinical trial with newborns shows that the inhibitor can be administered at any time point in the progression of postnatal hyperbilirubinemia to rapidly and predictably block heme degradation to bilirubin and prevent severe jaundice without significant short or long term side effects detected in treated infants (71).…”

Indoleamine 2,3 dioxygenase–mediated tryptophan catabolism regulates accumulation of Th1/Th17 cells in the joint in collagen‐induced arthritis

“…Because inhibition of NO production can ameliorate CIA depending on the time and route of delivery (36), it can be speculated that NO-IDO interactions limit the activation of IDO in the course of CIA. Similarly, HO-1-dependent generation of antioxidant compounds and consumption of the heme group can inhibit the activation of IDO, while inhibition of HO-1 has therapeutic effects in CIA (37,38).…”