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Arthritis suppression by NADPH activation operates through an interferon-beta pathway.

Olofsson P, Nerstedt A, Hultqvist M, Nilsson EC, Andersson S, Bergelin A, Holmdahl R - BMC Biol. (2007)

Bottom Line: 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).Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-1DA allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-1E3 rat (with an Ncf1E3 allele that allows a stronger oxidative burst).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 Ncf1 polymorphism.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biovitrum AB, Arvid Wallgrens Backe 20, Göteborg, Sweden. peter.olofsson@biovitrum.com

ABSTRACT

Background: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCF1), 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 NCF1-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-1DA allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-1E3 rat (with an Ncf1E3 allele that allows a stronger oxidative burst).

Conclusion: Naturally occurring genetic polymorphisms in the Ncf-1 gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-1 allele that enhances oxidative burst and protects against arthritis is operating through an IFN-beta-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 Ncf1 polymorphism.

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The relative mRNA expression of (A) Ass, (B) Cxcl9 and (C) Mmp12 in lymph nodes at 0, 3, 6, 8, 10, 13, 15 and 19 days after injection with pristane (circles) or phytol (squares). Values are means ± SEM from groups of four animals. Levels of significance were calculated using Student's t-test (*p < 0.05; **p < 0.01; ***p < 0.001).
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Figure 4: The relative mRNA expression of (A) Ass, (B) Cxcl9 and (C) Mmp12 in lymph nodes at 0, 3, 6, 8, 10, 13, 15 and 19 days after injection with pristane (circles) or phytol (squares). Values are means ± SEM from groups of four animals. Levels of significance were calculated using Student's t-test (*p < 0.05; **p < 0.01; ***p < 0.001).

Mentions: The three genes associated with increased expression after pristane administration (Ass, Cxcl9 and Mmp12) showed significantly increased expression (p < 0.01) after disease onset (i.e. days 13–19 after pristane administration) compared with the phytol-treated group. Phytol induced a small increase in expression of these genes around the day of disease onset (day 8–13) and then decreased to the same low expression as seen at day 0 (Figure 4). The fact that the highest expression of these genes occurs after arthritis onset makes it plausible that the increased expression of these genes is associated with the inflammatory response. However, as seen for the expression of Cxcl9 (Figure 4B), which also increased significantly (p < 0.05) at days 3–6 after pristane injection, the expression of such genes also plays a role in the early response after injection.


Arthritis suppression by NADPH activation operates through an interferon-beta pathway.

Olofsson P, Nerstedt A, Hultqvist M, Nilsson EC, Andersson S, Bergelin A, Holmdahl R - BMC Biol. (2007)

The relative mRNA expression of (A) Ass, (B) Cxcl9 and (C) Mmp12 in lymph nodes at 0, 3, 6, 8, 10, 13, 15 and 19 days after injection with pristane (circles) or phytol (squares). Values are means ± SEM from groups of four animals. Levels of significance were calculated using Student's t-test (*p < 0.05; **p < 0.01; ***p < 0.001).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC1884140&req=5

Figure 4: The relative mRNA expression of (A) Ass, (B) Cxcl9 and (C) Mmp12 in lymph nodes at 0, 3, 6, 8, 10, 13, 15 and 19 days after injection with pristane (circles) or phytol (squares). Values are means ± SEM from groups of four animals. Levels of significance were calculated using Student's t-test (*p < 0.05; **p < 0.01; ***p < 0.001).
Mentions: The three genes associated with increased expression after pristane administration (Ass, Cxcl9 and Mmp12) showed significantly increased expression (p < 0.01) after disease onset (i.e. days 13–19 after pristane administration) compared with the phytol-treated group. Phytol induced a small increase in expression of these genes around the day of disease onset (day 8–13) and then decreased to the same low expression as seen at day 0 (Figure 4). The fact that the highest expression of these genes occurs after arthritis onset makes it plausible that the increased expression of these genes is associated with the inflammatory response. However, as seen for the expression of Cxcl9 (Figure 4B), which also increased significantly (p < 0.05) at days 3–6 after pristane injection, the expression of such genes also plays a role in the early response after injection.

Bottom Line: 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).Importantly, these two molecular pathways were also confirmed to differentiate between the arthritis-susceptible dark agouti (DA) rat, (with an Ncf-1DA allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-1E3 rat (with an Ncf1E3 allele that allows a stronger oxidative burst).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 Ncf1 polymorphism.

View Article: PubMed Central - HTML - PubMed

Affiliation: Biovitrum AB, Arvid Wallgrens Backe 20, Göteborg, Sweden. peter.olofsson@biovitrum.com

ABSTRACT

Background: A polymorphism in the activating component of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex, neutrophil cytosolic factor 1 (NCF1), 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 NCF1-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-1DA allele that allows only low oxidative burst), and the arthritis-protected DA.Ncf-1E3 rat (with an Ncf1E3 allele that allows a stronger oxidative burst).

Conclusion: Naturally occurring genetic polymorphisms in the Ncf-1 gene modulate the activity of the NADPH oxidase complex, which strongly regulates the severity of arthritis. We now show that the Ncf-1 allele that enhances oxidative burst and protects against arthritis is operating through an IFN-beta-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 Ncf1 polymorphism.

Show MeSH
Related in: MedlinePlus