Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors.

Ralston, David R.; Marsh, Clay B.; Lowe, Melissa P.; Wewers, Mark D.

doi:10.1172/jci119662

Cited by 168 publications

(97 citation statements)

References 19 publications

(21 reference statements)

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“…Of note, previous studies revealed that proteinase 3 antineutrophil cytoplasmic antibodies (PR3 ANCA) induce IL-8 release by human peripheral blood monocytes through binding to PR3 expressed on the surface of monocytes (10). It remains unclear whether PR3 ANCA upregulate expression of IL-8 mRNA in monocytes or simply induce release of preformed IL-8 from monocytes.…”

Section: Discussionmentioning

confidence: 99%

“…It remains unclear whether PR3 ANCA upregulate expression of IL-8 mRNA in monocytes or simply induce release of preformed IL-8 from monocytes. Because Fab or F(abЈ) 2 fragments of anti-PR3 IgG did not induce IL-8 release, the induction of IL-8 release was considered to involve Fc␥R crosslinking (10). In contrast, in the present study F(abЈ) 2 fragments of anti-P antibodies up-regulated expression of TNF␣ and IL-6 in * Highly purified monocytes (1 ϫ 10 6 /ml) were cultured in the presence of affinity-purified IgG anti-ribosomal P (anti-P), F(abЈ) 2 anti-P (affinity-purified anti-P from F[abЈ] 2 fragments of total IgG), or control IgG (3 g/ml).…”

Section: Discussionmentioning

confidence: 99%

“…Because the ribosomal P epitope is expressed on endothelial cells (10), further studies to examine the direct effects of anti-P antibodies on the functions of endothelial cells would be helpful for complete understanding of the pathogenic role of anti-P antibodies. Finally, although the current studies demonstrate the direct interactions of anti-P antibodies with monocytes to up-regulate their expression of IL-6 and TNF␣ mRNA, further studies using monocytes from SLE patients would be required to explore the in vivo relevance of our observations.…”

Section: Discussionmentioning

confidence: 99%

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Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Nagai¹,

Arinuma²,

Yanagida³

et al. 2005

Arthritis & Rheumatism

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Objective. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with systemic lupus erythematosus (SLE) and have been found to be associated with some manifestations of the disease, including lupus psychosis and hepatitis. Recent studies have disclosed that anti-P antibodies react with activated T cells but not with B cells, suggesting possible direct effects of anti-P antibodies on immune regulation. The present study was designed to explore the presence of the epitope recognized by anti-P antibodies on human peripheral blood monocytes.Methods. Highly purified peripheral blood monocytes obtained from healthy donors were cultured with or without interferon-␥ (IFN␥) in the presence of either anti-P antibodies purified by affinity chromatography from the sera of patients with SLE or control IgG.Results. Flow cytometry analysis disclosed that fresh (day 0) monocytes did not express the ribosomal P epitope, whereas expression of the ribosomal P epitope was induced on annexin V-negative monocytes after activation through plastic adherence for 48 hours. More important, anti-P antibodies (compared with normal IgG or IgG from SLE patients devoid of anti-P antibodies) enhanced the production of tumor necrosis factor ␣ (TNF␣) and interleukin-6 (IL-6) by activated monocytes. Accordingly, anti-P antibodies also up-regulated the expression of TNF␣ and IL-6 messenger RNA in activated monocytes. Of note, F(ab ) 2 fragments of anti-P antibodies, which do not result in Fc␥ receptor (Fc␥R) crosslinking, also effectively up-regulated the expression of TNF␣ and IL-6.Conclusion. These results indicate that human peripheral blood monocytes express the ribosomal P epitope upon activation, irrespective of induction of apoptosis. Moreover, the data suggest that anti-P antibodies might modify a variety of inflammatory responses through up-regulation of the expression of proinflammatory cytokines in monocytes, in a manner that does not involve Fc␥R crosslinking.Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by the expression of a variety of autoantibodies. Autoantibodies to ribosomal P proteins (anti-P antibodies) are detected in 12-16% of patients with SLE (1). Anti-P antibodies are directed to 3 phosphoproteins (P0, P1, and P2), which are located on the larger 60S subunit of eukaryotic ribosomes and have molecular weights of 38 kd, 19 kd, and 17 kd, respectively (1). Ribosomal P proteins share a common linear determinant that is present in the carboxyl-terminal 22-amino acid sequence (1). Previous and recent studies have disclosed the association of anti-P antibodies with neuropsychiatric disease in SLE (2,3). Moreover, it was recently shown that antiribosomal P is strongly associated with hepatitis and

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Nagai¹,

Arinuma²,

Yanagida³

et al. 2005

Arthritis & Rheumatism

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“…7 and 8). For example, the addition of exogenous AAT in vitro inhibits the release of IL-8 by monocytes (9) and the expression of HIV-1 (10). In animal models, the administration of AAT prevents murine islet cell allografts from rejection (11), blocks β-cell apoptosis (12), and suppresses alloreactivity in allogeneic marrow transplantation models (13,14).…”

mentioning

confidence: 99%

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

Jonigk

Al-Omari²,

Maegel

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

215

148

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The rationale of α1-antitrypsin (AAT) augmentation therapy to treat progressive emphysema in AAT-deficient patients is based on inhibition of neutrophil elastase; however, the benefit of this treatment remains unclear. Here we show that clinical grade AAT (with elastase inhibitory activity) and a recombinant form of AAT (rAAT) without anti-elastase activity reduces lung inflammatory responses to LPS in elastase-deficient mice. WT and elastasedeficient mice treated with either native AAT or rAAT exhibited significant reductions in infiltrating neutrophils (23% and 68%), lavage fluid levels of TNF-α (70% and 80%), and the neutrophil chemokine KC (CXCL1) (64% and 90%), respectively. Lung parenchyma TNF-α, DNA damage-inducible transcript 3 and X-box binding protein-1 mRNA levels were reduced in both mouse strains treated with AAT; significantly lower levels of these genes, as well as IL-1β gene expression, were observed in lungs of AAT-deficient patients treated with AAT therapy compared with untreated patients. In vitro, LPS-induced cytokines from WT and elastasedeficient mouse neutrophils, as well as neutrophils of healthy humans, were similarly reduced by AAT or rAAT; human neutrophils adhering to endothelial cells were decreased by 60-80% (P < 0.001) with either AAT or rAAT. In mouse pancreatic islet macrophages, LPS-induced surface expression of MHC II, Toll-like receptor-2 and -4 were markedly lower (80%, P < 0.001) when exposed to either AAT or rAAT. Consistently, in vivo and in vitro, rAAT reduced inflammatory responses at concentrations 40-to 100-fold lower than native plasma-derived AAT. These data provide evidence that the anti-inflammatory and immunomodulatory properties of AAT can be independent of elastase inhibition.is the prototypic member of the serpin superfamily and one of the most abundant serine protease inhibitors in the circulation (1). As an acute-phase protein, AAT is thought to play an important role in limiting host-tissue injury triggered by proteases, particularly neutrophil elastase (NE). The clinical relevance of AAT is highlighted in individuals with inherited deficiency in circulating AAT, who have increased susceptibility to early-onset pulmonary emphysema, liver and pancreatic diseases, and in rare cases to panniculitis and vasculitis (2). It has been assumed that in AAT-deficiency the protease/antiprotease balance is shifted toward NE, which leads to extensive tissue damage, particularly in causing emphysema. Therefore, augmentation of circulating AAT was introduced 25 y ago to treat emphysema patients with severe PiZZ (Glu342Lys) AAT deficiency (3). Because clinical trials of AAT augmentation therapy use historical data as controls, the benefit of AAT therapy for PiZZ patients remains under debate (4-6), although in most cases therapy offers disease stabilization. The uncertainty surrounding the efficacy of augmentation therapy also reflects the incomplete understanding of the properties of the AAT protein, which can be affected by the isolation methods from plasma.Although the a...

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“…6). A lesser number of in vitro studies clearly show that ANCA also can activate monocytes (6)(7)(8)(9)(10). Multiple animal models support a pathogenic role for ANCA in vivo (11).…”

mentioning

confidence: 99%

ANCAs Are Also Antimonocyte Cytoplasmic Autoantibodies

Jennette

Falk

2015

Clinical Journal of the American Society of Nephrology

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Antineutrophil cytoplasmic antibodies induce monocyte IL-8 release. Role of surface proteinase-3, alpha1-antitrypsin, and Fcgamma receptors.

Cited by 168 publications

References 19 publications

Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Anti–ribosomal P protein antibody in human systemic lupus erythematosus up‐regulates the expression of proinflammatory cytokines by human peripheral blood monocytes

Anti-inflammatory and immunomodulatory properties of α1-antitrypsin without inhibition of elastase

ANCAs Are Also Antimonocyte Cytoplasmic Autoantibodies

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