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Arthritis suppressi...
Arthritis suppression by NADPH activation operates through an interferon-beta pathway
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Olofsson, Peter (author)
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Nerstedt, Annika (author)
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- Hultqvist, Malin (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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Nilsson, Elisabeth C. (author)
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Andersson, Sofia (author)
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- Bergelin, Anna (author)
- Biovitrum AB, Göteborg, Sweden
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- Holmdahl, Rikard (author)
- Lund University,Lunds universitet,Immunologi,Forskargrupper vid Lunds universitet,Immunology,Lund University Research Groups
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(creator_code:org_t)
- 2007-05-09
- 2007
- English.
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In: BMC Biology. - : Springer Science and Business Media LLC. - 1741-7007. ; 5
- Related links:
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http://dx.doi.org/10...
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https://bmcbiol.biom...
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https://doi.org/10.1...
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https://lup.lub.lu.s...
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https://doi.org/10.1...
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https://urn.kb.se/re...
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Abstract
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- Background: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCFI), has previously been identified as a regulator of arthritis severity in mice and rats. This discovery resulted in a search for NADPH oxidase- activating substances as a potential new approach to treat autoimmune disorders such as rheumatoid arthritis (RA). We have recently shown that compounds inducing NCFI- dependent oxidative burst, e. g. phytol, have a strong ameliorating effect on arthritis in rats. However, the underlying molecular mechanism is still not clearly understood. The aim of this study was to use gene- expression profiling to understand the protective effect against arthritis of activation of NADPH oxidase in the immune system. Results: Subcutaneous administration of phytol leads to an accumulation of the compound in the inguinal lymph nodes, with peak levels being reached approximately 10 days after administration. Hence, global gene- expression profiling on inguinal lymph nodes was performed 10 days after the induction of pristane-induced arthritis (PIA) and phytol administration. The differentially expressed genes could be divided into two pathways, consisting of genes regulated by different interferons. IFN-gamma regulated the pathway associated with arthritis development, whereas IFN-beta regulated the pathway associated with disease protection through phytol. Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-/(DA) allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-/(E3) rat (with an Ncf/(E3) allele that allows a stronger oxidative burst). Conclusion: Naturally occurring genetic polymorphisms in the Ncf-/ gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-/ allele that enhances oxidative burst and protects against arthritis is operating through an IFN-gamma-associated pathway, whereas the arthritis-driving allele operates through an IFN-gamma-associated pathway. Treatment of arthritis- susceptible rats with an NADPH oxidase- activating substance, phytol, protects against arthritis. Interestingly, the treatment led to a restoration of the oxidative- burst effect and induction of a strikingly similar IFN-beta-dependent pathway, as seen with the disease-protective Ncfl polymorphism.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Immunology in the medical area (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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