Chemical induction of HO-1 suppresses lupus nephritis by reducing localiNOS expression and synthesis of anti-dsDNA antibody

Abstract

SUMMARYThere is accumulating evidence that haem oxygenase (HO)-1 plays a protective role in various disorders. The beneficial efficacy of HO-1 induction therapy has been shown in renal diseases such as glomerulonephritis, interstitial nephritis and drug induced nephrotoxicity. However, involvement of HO-1 in the development of autoimmune renal diseases remains uncertain. To assess the clinical efficacy of HO-1 induction therapy for lupus glomerulonephritis, MRL/ lpr mice were intraperitoneally injected with 100 m mol/kg hemin, a potent HO-1 inducer, or PBS as controls, once a week from 6 weeks of age to 21-24 weeks-old. We found that treatment with hemin led to a significant reduction of proteinuria and remarkable amelioration of glomerular lesions accompanied by decreased immune depositions. In addition, the circulating IgG anti-double-stranded DNA antibody level was significantly decreased in hemin treated mice when compared with controls. A single intraperitoneal injection with hemin resulted in reduction of inducible nitric oxide synthase expression in the kidney and spleen, and serum interferong level. Our results suggest that HO-1 induction therapy ameliorates lupus nephritis by suppressing nitric oxide (NO) dependent inflammatory responses and attenuating production of pathogenic autoantibodies.Keywords haem oxygenase-1 (HO-1) MRL/ lpr inducible nitric oxide synthase ( i NOS) interferon-gamma (IFN-g )

HO‐1 promoter polymorphism associated with rheumatoid arthritis

“…3956 RUEDA ET AL several autoimmune disorders such as RA, inflammatory bowel disease, systemic lupus erythematosus, and multiple sclerosis (7,8,11,22).…”

“…All the activities mentioned above suggest that HO-1 is a protective molecule. In fact, HO-1 induction shows beneficial effects in cardiovascular disease, transplantation, acute inflammation, and autoimmune disorders (4)(5)(6)(7)(8).…”

Wearing Red for Signaling: The Heme-Bach Axis in Heme Metabolism, Oxidative Stress Response and Iron Immunology

“…Examples include NADPH oxidases, which are heme enzymes (Sumimoto 2008). The induction and absence of HO-1 have been shown to modify the immune system (Woo et al 1998;Kapturczak et al 2004;Takeda et al 2004;Chauveau et al 2005;McDaid et al 2005;Matsushima et al 2009;Tzima et al 2009;Schumacher et al 2012;So et al 2012). However, the mechanisms underlying the HO-1-mediated modulation of the immune system remain elusive (Soares et al 2009).…”

Regulatory role of heme oxygenase 1 in inflammation of rheumatoid arthritis

“…These cytoprotective functions can be applied for therapeutic purposes. We previously reported that chemical induction of HO-1 suppresses lupus nephritis (15) and that adenovirus vector-mediated gene transfer of HO-1 complementary DNA (cDNA) has beneficial effects on lipopolysaccharide (LPS)-induced lung injury (16), influenza viral pneumonia (17), bleomycin-induced pulmonary fibrosis (18), Pseudomonas chronic respiratory infection (19), and elastase-induced emphysema (20) in mouse models. Similarly, favorable outcomes have been achieved with therapies using HO-1 chemical inducers or with gene transfer in other animal models, including ischemia/ reperfusion-induced injuries of the heart (9) and liver (21), LPS-induced ocular inflammation (22), and allogenic heart allotransplantation (23).…”