Heme oxygenase-1 (HO-1) exerts its functions via the catabolism of heme into carbon monoxide (CO), Fe 2؉ , and biliverdin, as well as by depletion of free heme. We have recently described that overexpression of HO-1 is associated with the tolerogenic capacity to dendritic cells (DCs) stimulated by LPS. In this study, we demonstrate that treatment of human monocytederived DCs with CO blocks TLR3 and 4-induced phenotypic maturation, secretion of proinflammatory cytokines, and alloreactive T cell proliferation, while preserving IL-10 production. Treatment of DCs with biliverdin, bilirubin, and deferoxamine or replenishing intracellular heme stores had no effect on DC maturation. HO-1 and CO inhibited LPS-induced activation of the IFN regulatory factor 3 pathway and their effects were independent of p38, ERK, and JNK MAPK. H eme oxygenases are the rate-limiting enzymes in the catabolism of heme, yielding equimolar amounts or carbon monoxide (CO), 5 free iron, and biliverdin (BV) (1), which is subsequently reduced into bilirubin (BL). Heme oxygenase 1 (HO-1), the inducible form of heme oxygenases, has protective effects in a variety of experimental inflammatory models (reviewed in Ref.2). The physiological importance of HO-1 has been demonstrated in both mice and humans, where HO-1 deficiency resulted in a progressive and chronic inflammation and a reduced cellular resistance to oxidative stress (3-5). Induction of HO-1 expression by pharmacological activators or gene transfer have therapeutic effects in a variety of conditions or disorders involving inflammation and immune responses, including organ transplantation and autoimmunity (6 -12). In several models, CO mimics the effects of HO-1 (reviewed in Ref. 13), indicating that HO-1 acts via the generation of CO. However, other end products of HO-1 activity, such as BV (14), free iron depletion by increased H chain ferritin expression (15), or cellular efflux pumps (16), or heme depletion (17) can also mediate the effects of HO-1.Dendritic cells (DCs) play a major role in the initiation and regulation of the immune response. They have distinct stages of cell development, activation, and maturation and have the potential to induce both immunity and tolerance (reviewed in Ref. 18). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues continuously capture innocuous and cell-associated self-Ags and migrate to draining lymph nodes where they can induce tolerance (19). In the presence of danger and TLR signals, DCs mature, acquiring the ability to stimulate differentiation of naive T cells into effector cells. In certain conditions, phenotypically mature DCs have tolerogenic functions (18).We previously showed that human and rat iDCs express HO-1, that this expression is restricted to certain DC populations, and that HO-1 expression drastically decreases upon DC maturation (20). We and others have demonstrated that overexpression of HO-1 in DCs inhibits their LPS-induced maturation and proinflammatory functions (20,21), and it has been recently...

Despite widespread usage of β-adrenergic receptor (AR) agonists and antagonists in current clinical practice, our understanding of their interactions with the immune system is surprisingly sparse. Among the AR expressed by dendritic cells (DC), β2-AR can modify in vitro cytokine release upon stimulation. Because DC play a pivotal role in CD8+ T cell immune responses, we examined the effects of β2-AR stimulation on MHC class I exogenous peptide presentation and cross-presentation capacities. We demonstrate that β2-AR agonist-exposed mature DC display a reduced ability to cross-present protein Ags while retaining their exogenous peptide presentation capability. This effect is mediated through the nonclassical inhibitory G (Gαi/0) protein. Moreover, inhibition of cross-presentation is neither due to reduced costimulatory molecule expression nor Ag uptake, but rather to impaired phagosomal Ag degradation. We observed a crosstalk between the TLR4 and β2-AR transduction pathways at the NF-κB level. In vivo, β2-AR agonist treatment of mice inhibits Ag protein cross-presentation to CD8+ T cells but preserves their exogenous MHC class I peptide presentation capability. These findings may explain some side effects on the immune system associated with stress or β-agonist treatment and pave the way for the development of new immunomodulatory strategies.