Heme oxygenase-1 (HO-1) is an intracellular enzyme that degrades heme and inhibits immune responses and inflammation in vivo. In most cell types, HO-1 is inducible by inflammatory stimuli and oxidative stress. Here we demonstrate that human monocyte-derived immature dendritic cells (iDCs) and several but not all freshly isolated rat splenic DC subsets and rat bone marrow-derived iDCs, spontaneously express HO-1. HO-1 expression drastically decreases during human and rat DC maturation induced in vitro. In IntroductionHeme oxygenases (HOs) are the rate-limiting intracellular enzymes that degrade heme to biliverdin, free divalent iron, and CO (for a review, see Otterbein and Choi 1 ). Three distinct HO enzymes have been identified: HO-1, HO-2, and HO-3. 1 HO-1 is a stress responsive gene whose expression is induced by a variety of stimuli including heme, heavy metals, inflammatory cytokines, and nitric oxide. 1 HO-1 is known for its cytoprotective effect against oxidative injuries and inflammation. 1 Induction of HO-1 expression by pharmacologic activators or gene transfer has had therapeutic effects in a variety of conditions or disorders involving the immune system, including transplantation and inflammatory disorders. [2][3][4][5][6][7][8] Biliverdin and its metabolite, bilirubin, are known for their antioxidant 9 and immunosuppressive effects. 10 HO-1 and CO have been shown to inhibit lipopolysaccharide (LPS)-induced expression of proinflammatory cytokines and to increase LPS-induced expression of interleukin 10 (IL-10) in macrophages. 11,12 Moreover, IL-10 induces HO-1 expression in macrophages. [13][14][15] We previously reported that overexpression of HO-1, obtained with an HO-1-encoding adenovirus in rats having heart transplants, results in long-term allograft survival associated with an inhibition of cellular allogeneic immune responses, which could be mediated by adenoviral transduction of dendritic cells (DCs). 6 DCs play a central role in the induction of immunity and tolerance (for a review, see Steinman et al 16 ). In the absence of inflammation, immature DCs (iDCs) located in peripheral tissues specialize in taking up innocuous and cell-associated self antigens.They continuously capture antigens and migrate to draining lymph nodes where they can induce tolerance. 16 In the presence of danger signals, DCs undergo maturation, a process involving upregulation of surface major histocompatibility complex (MHC) class II and costimulatory molecules, secretion of proinflammatory and anti-inflammatory cytokines, and the acquired ability to stimulate differentiation of naive T cells into effector cells.Our working hypothesis was that DCs can express HO-1, which can regulate DC functions. In this study, we demonstrate that human and rat iDCs express HO-1 and that HO-1 expression is down-regulated by maturation stimuli. Our results also demonstrate that induction of HO-1 expression renders DCs refractory to LPS-induced maturation, but preserves IL-10 secretion, suggesting that HO-1 may be used to regulate DC f...

Purpose: Malignant mesothelioma is a highly aggressive tumor and is often diagnosed too late for a curative treatment.We compared diagnostic and prognostic values of mesothelin and osteopontin in172 patients suspected of malignant pleural mesothelioma (MPM) and in a control group of 112 asymptomatic asbestos-exposed subjects. Experimental Design: Osteopontin and mesothelin were assayed with commercial ELISA kits in a series of 43 patients with pleural metastases of various carcinomas, 33 patients with benign pleural lesions associated with asbestos exposure, 96 patients with MPMs, and 112 asbestosexposed healthy subjects. Results were correlated with patient's diagnosis and survival. Results: Serum osteopontin level was higher in MPM patients compared with healthy asbestosexposed subjects and had a good capability to distinguish between these two populations. However, osteopontin was unable to distinguish between MPM and pleural metastatic carcinoma or benign pleural lesions associated with asbestos exposure. Neither plasma nor pleural fluid osteopontin were more powerful in this respect. Serum mesothelin had a good ability for diagnosing MPM but was unable to identify patients with nonepithelioid mesothelioma subtypes. Survival analysis identified tumor histologic subtype along with serum osteopontin and serum mesothelin as independent prognostic factors in mesothelioma patients. Conclusions: Osteopontin has a lower diagnostic accuracy than mesothelin in patients suspected of MPM. Insufficient specificity limits osteopontin utility as diagnostic marker. Both molecules have a potential value as prognostic markers.

We show that SMRPs may be a promising marker for mesothelioma diagnosis when measured either in serum or pleural fluid. The diagnostic value of SMRPs was similar in both types of samples, but pleural fluid SMRPs may better discriminate mesothelioma from pleural metastasis.