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Relationship: 2053
Title
Increased proinflammatory mediators leads to Increased transcription of genes encoding acute phase proteins
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Substance interaction with lung resident cell membrane components leading to atherosclerosis | adjacent | High | Moderate | Ulla Vogel (send email) | Under development: Not open for comment. Do not cite | Under Development |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Male | High |
Female | High |
Life Stage Applicability
Term | Evidence |
---|---|
All life stages | High |
Key Event Relationship Description
This KER presents the association between the secretion of pro-inflammatory mediators (Key event 1496) and transcription of genes encoding acute phase proteins (f. ex. Saa1, Saa2 and Saa3) (Key event 1438) in different tissues, mainly lung and liver. Pro-inflammatory mediators are the secondary messengers that initiate and regulate inflammatory reactions. They are secreted during inflammation in all species. Acute phase proteins are proteins that have an increase in plasma concentration of at least 25% during an acute phase response (Gabay & Kushner, 1999). Acute phase proteins are induced by pro-inflammatory mediators (f. ex. IL-6, TNF-α and IL-1β) and their genes are expressed mainly in the liver, but also in several other tissues (Gabay & Kushner, 1999; Urieli-Shoval et al., 1998). The evidence of the KER presented is based on in vitro studies, animal studies (mice) and human studies.
Evidence Collection Strategy
This KER is considered canonical knowledge and supporting evidence was assembled from literature search on the search engine PubMed.
Evidence Supporting this KER
Biological Plausibility
The biological plausibility is high. It is known that acute phase proteins are induced by pro-inflammatory cytokines, primary interleukin (IL)-6, IL-1β, and tumor necrosis factor α (TNF-α). These cytokines are produced at sites of inflammation, mainly by monocytes and macrophages (Gabay & Kushner, 1999; Mantovani & Garlanda, 2023; Uhlar & Whitehead, 1999; Venteclef, Jakobsson, Steffensen, & Treuter, 2011). Following cytokine release, signaling cascades and transcription factors are activated, regulating the expression of acute phase reaction genes (Venteclef et al., 2011).
In this KER, pulmonary inflammation has been considered as an indirect marker of the release of pro-inflammatory factors because the release of inflammatory mediators (i.e. cytokines and chemokines) recruits immune cells to inflammation sites (Janeway, Murphy, Travers, & Walport, 2008). In mice, pulmonary inflammation is commonly assessed as the number or fraction of neutrophils in the broncheoalveolar lavage fluid (BALF) (Van Hoecke, Job, Saelens, & Roose, 2017).
Empirical Evidence
- Interleukin (IL)-1 (IL-1α and IL-1β, 10 ng/mL each) and IL-6 (500 units/mL), both in presence of 1 µM dexamethasone, increased the relative levels of serum amyloid A (SAA) mRNA in cultured human adult aortic smooth muscle cells (Meek, Urieli-Shoval, & Benditt, 1994).
- Human hepatoma cells exposed to IL-6, IL-1β and tumor necrosis factor α (TNF-α) for 20 h showed a reduced synthesis of albumin and increased synthesis of the acute phase proteins C3 and ceruloplasmin. In addition, mice exposed to IL-1β and TNF-α showed an increase of Saa mRNA in liver tissue (Ramadori, Van Damme, Rieder, & Meyer zum Buschenfelde, 1988).
- After pulmonary exposure to lipopolysaccharide (LPS) (300 µg/mL), lung tissue from female C57BL/6 mice showed upregulation of several cytokines and chemokines genes and upregulation of the acute phase proteins genes Saa and α1-protease inhibitor (Jeyaseelan, Chu, Young, & Worthen, 2004).
- Mice presenting IL-6 gene disruption (IL-6-/-) shown a reduced response in liver mRNA levels of acute phase proteins haptoglobin, α1-acid glycoprotein and SAA, after challenged by turpentine, LPS and bacterial infection (Kopf et al., 1994).
- After repeated instillation of carbon black nanoparticles, female C57BL/6BomTac mice showed increased expression of chemokine genes along with increased Saa3 gene expression in lung tissue. In addition, dose-response relationships with several cytokine proteins were identified in lung tissue (Jackson et al., 2012).
- Intratracheal instillation of titanium dioxide in female C57BL/6 mice showed that 28 days after exposure, several genes of cytokines, chemokines and acute phase proteins were upregulated. Additionally, there were significant increases in inflammatory mediators in lung tissue (Husain et al., 2013).
The table below presents evidence of the KER using neutrophil numbers in broncheoalveolar lavage fluid (BALF) as indirect evidence of the release of pro-inflammatory mediators (Key event 1496), while the transcription of genes encoding acute phase proteins was measured in tissues (Key event 1438).
Species |
Stressor |
Secretion of pro-inflammatory mediators |
Transcription of genes encoding acute phase proteins |
Reference |
Mouse |
Ultrafine carbon particles |
No significant increase in polymorphonuclear cells (includes neutrophils) in BALF. |
Yes, increased Saa3 gene expression at 24 h. |
(Andre et al., 2006) |
Mouse |
Diesel exhaust particles |
Yes, significant increase of neutrophils in BALF. |
Yes, increased expression of Saa3 genes in lung tissue. No expression of Sap, Saa1 or Saa3 genes on liver tissue. |
(Saber et al., 2005, 2009, 2013) |
Mouse |
Titanium dioxide nanoparticles |
Yes, significant increased numbers of neutrophils in BALF. |
Yes, increased expression of Saa1 and Saa3 genes in lung tissue |
(Halappanavar et al., 2011; Hougaard et al., 2010) |
Mouse |
Carbon black nanoparticles |
Yes, significant increase of neutrophil number 1, 3 and 28 days after exposure. |
Yes, significant Saa1, Saa2 and Saa3 gene expression increase in lung tissue, at days 1, 3 and 28 after exposure. Saa3 gene expression increase in liver tissue at day 1 after exposure. |
(Bourdon, Halappanavar, et al., 2012; Bourdon, Saber, et al., 2012) |
Mouse |
Titanium dioxide nanoparticles |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 µg, and 1, 3 and 28 days after exposure to 162 µg. |
Yes, increased mRNA expression of Saa3 in lung issue at days 1, 3 and 28 after exposure with 162 µg, and at day 3 with 54 µg. |
(Saber et al., 2012, 2013) |
Mouse |
Carbon black nanoparticles |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 54 and 162 µg, and 1 and 3 days after exposure to 18 µg. |
Yes, increased mRNA expression of Saa3 in lung issue at days 1, 3 and 28 after exposure with 54 µg and 162 µg, and at days 1 and 3 with 18 µg. |
(Saber et al., 2012, 2013) |
Mouse |
Diesel exhaust particles |
Yes, increased neutrophil numbers in BALF 3 days after exposure to 54 µg, and 1 and 3 days after exposure to 162 µg. |
Yes, increased Saa3 gene expression after 1, 3 and 28 days with 162 µg, at day 28 with 54 µg, and at day 3 with 18 µg. |
(Kyjovska et al., 2015) |
Mouse |
Multiwalled carbon nanotubes (referred as CNTsmall) |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 18, 54 and 162 μg. |
Yes, increased differential expression of acute phase response genes in lung and liver tissue. |
(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015) |
Mouse |
Multiwalled carbon nanotubes (referred as CNTlarge) |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 18, 54 and 162 μg. |
Yes, increased differential expression of acute phase response genes in lung and liver tissue. |
(Poulsen, Saber, Mortensen, et al., 2015; Poulsen, Saber, Williams, et al., 2015) |
Mouse |
Sanding dust from epoxy composite containing carbon nanotubes |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54, 162 and 486 μg, and 28 days after exposure to 486 μg. |
Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 486 μg). |
(Saber et al., 2016) |
Mouse |
Sanding dust from epoxy composite without carbon nanotubes |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 54, 162 and 486 μg, 3 days after exposure to 162 and 486 μg, and 28 days after exposure to 486 μg. |
Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 486 μg). |
(Saber et al., 2016) |
Mouse |
Carbon nanotubes |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 after exposure to 18, 54 and 162 μg. |
Yes, significant increase in Saa1 mRNA expression in liver tissue (only assessed 1 days after exposure to 162 μg). |
(Saber et al., 2016) |
Mouse |
Graphene oxide |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg. |
Yes, increased mRNA expression of Saa3 in lung tissue, at all dose 1 and 3 days after exposure. Increased gene expression of Saa1 in liver tissue 1 day after exposure to 18 µg, and 3 days after exposure to 162 µg. |
(Bengtson et al., 2017) |
Mouse |
Reduced graphene oxide |
Yes, increased neutrophil numbers 1 and 3 days after exposure to 162, and 90 days after exposure to 18, 54 and 162 μg. |
Yes, increased mRNA expression of Saa3 in lung tissue, 3 days after exposure to 162 µg. No changes in gene expression of Saa1 in liver tissue. |
(Bengtson et al., 2017) |
Mouse |
Carbon black |
Yes, increased neutrophil numbers in BALF 1, 3, 28 and 90 days after exposure. |
Yes, increased mRNA expression of Saa3 in lung tissue 1, 3, 28 and 90 days after exposure. Increased gene expression of Saa1 in liver tissue 1 day after exposure. |
(Bengtson et al., 2017) |
Mouse |
Unmodified rutile (TiO2) |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 and 162 μg, and 28 days after exposure to 162 μ. |
Yes, increased expression of Saa3 mRNA in lung tissue 1, 3 and 28 days after exposure to 162 µg. Increased expression of Saa1 in liver tissue 1 day after exposure to 162 µg and 3 days after exposure to 54 and 162 µg. |
(Wallin et al., 2017) |
Mouse |
Surface modified rutile (TiO2) |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 54 and 162 μg. |
Yes, increased expression of Saa3 mRNA in lung tissue 1, and 28 days after exposure to 54 µg, and 1, 3 and 28 days after exposure to 162 µg. Increased expression of Saa1 in liver tissue 1 day after exposure to 162 µg. |
(Wallin et al., 2017) |
Mouse |
Particulate matter from non-commercial airfield |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 18 and 54 µg. |
Yes, increased expression of Saa3 mRNA in lung tissue and Saa1 mRNA in liver tissue after 1 day of exposure to 54 µg. No effect after 28 and 90 days. |
(Bendtsen et al., 2019) |
Mouse |
Particulate matter from commercial airport |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 18 and 54 µg. |
Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 18 and 54 µg. No effect after 28 and 90 days. |
(Bendtsen et al., 2019) |
Mouse |
Diesel exhaust particles |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 and 162 µg, and 28 days after exposure to 162 μg. |
Yes, increased expression of Saa3 mRNA in lung tissue after 1 day of exposure to 54 and 162 µg, and increased expression of Saa1 mRNA in liver tissue 1 day after exposure to 162 µg. No effect after 28 days. |
(Bendtsen et al., 2019) |
Mouse |
Carbon black |
Yes, increased neutrophil in BALF after 1, 28 and 90 days of exposure. |
Yes, increased expression of Saa3 mRNA in lung tissue at day 1 and day 90. |
(Bendtsen et al., 2019) |
Mouse |
Coated zinc oxide nanoparticles |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 2 µg, and 28 days after exposure to 0.2 and 0.7 µg. |
Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 0.7 and 2 µg. No effect 3 and 28 days after exposure. |
(Hadrup et al., 2019) |
Mouse |
Surface modified hallosytes |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 54 μg, and 28 days after exposure to 6 and 54 μg. |
Yes, increase Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to 54 µg. No effect on Saa1 mRNA expression on liver tissue. |
(Barfod et al., 2020) |
Mouse |
Carbon black |
Yes, increased neutrophil numbers in BALF 1, 3 and 28 days after exposure to 162 μg. |
Yes, increase Saa3 mRNA expression in lung tissue 1, 3 and 28 days after exposure. No effect on Saa1 mRNA expression on liver tissue. |
(Barfod et al., 2020) |
Mouse |
Nanofil9 (Organomodified nanoclay) |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 µg, and 3 days after exposure to 18 and 54 µg. |
Yes, increased Saa3 mRNA expression in lung tissue 1 day after exposure to all doses, and 3 days after exposure to 6 and 18 µg. |
(Di Ianni et al., 2020) |
Mouse |
NanofilSE3000 (Organomodified nanoclay) |
Yes, increased neutrophil numbers in BALF 1 day after exposure to 54 and 162 µg, and 3 days after exposure to 162 µg. |
Yes, increased Saa3 mRNA expression in lung tissue 1 day after exposure to 54 and 162 µg, and 3 days after exposure to 54 µg. |
(Di Ianni et al., 2020) |
Mouse |
Bentonite |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg. |
Yes, increased Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to all doses, and 28 days after exposure to 162 µg. |
(Di Ianni et al., 2020) |
Mouse |
Carbon black |
Yes, increased neutrophil numbers in BALF 1 and 3 days after exposure to 18, 54 and 162 µg, and 28 day after exposure to 162 µg. |
Yes, increased Saa3 mRNA expression in lung tissue 1 and 3 days after exposure to all doses, and 28 days after exposure to 54 and 162 µg. |
(Di Ianni et al., 2020) |
Additional evidence can be found in the following link: Additional evidence KER 2053_1 and Additional evidence KER 2053_2.
Uncertainties and Inconsistencies
The table below presents inconsistencies for this KER, where secretion of pro-inflammatory mediators has been observed after exposure to a stressor, while systemic acute phase response was not observed, or viceversa. Secretion of pro-inflammatory mediators was measured as change in concentration of pro-inflammatory markers in blood or increase neutrophil numbers in bronchoalveolar lavage fluid (BALF), while the transcription of genes encoding acute phase proteins was measured in tissues.
Species |
Stressor |
Secretion of pro-inflammatory mediators |
Transcription of genes encoding acute phase proteins |
Reference |
Mouse |
Carbon black |
No significant increase of neutrophils in BALF. |
Yes, increased expression of Saa3 gene in lung tissue. No expression of Sap, Saa1 or Saa3 genes on liver tissue. |
(Saber et al., 2005, 2009, 2013) |
Mouse |
Uncoated zinc oxide nanoparticles |
No increase of neutrophil numbers in BALF after exposure. |
Yes, increase on Saa3 mRNA in lung tissue 1 day after exposure to 2 µg. No effect 3 and 28 days after exposure. |
(Hadrup et al., 2019) |
Mouse |
Unmodified hallosytes |
Yes, increased neutrophil numbers in BALF 28 days after exposure to 18 μg. |
No effect on Saa3 mRNA expression in lung tissue nor Saa1 mRNA expression in liver tissue. |
(Barfod et al., 2020) |
Mouse |
Aluminum oxide |
Yes, increased neutrophil numbers in BALF 1 and 28 days after exposure to 54 µg. |
No change in Saa3 mRNA expression in lung tissue. |
(Gutierrez et al., 2023) |
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Neutrophil number in brochoalveolar lavage fluid (indirect measure of the secretion of proinflammatory mediators (Key event 1496) correlates with the expression of Saa3 mRNA levels in lung tissue (Key event 1438), in female C57BL/6J mice 1 and 28 days after intratracheal instillation of metal oxide nanomaterials (Figure 1). The Pearson’s correlation coefficient was 0.82 (p<0.001) between log-transformed neutrophil numbers in brochoalveolar lavage fluid and log-transformed Saa3 mRNA levels in lung tissue (Gutierrez et al., 2023).
Figure 1. Correlations between neutrophil numbers and Saa3 mRNA levels in lung tissue, including data from 1 and 28 days after exposure to nanomaterials. Reproduced from Gutierrez et al. (2023).
Time-scale
It has been shown that pro-inflammatory mediators concentrations increase before the expression of genes enconding acute phase proteins:
- Upregulation of cytokine genes [Interleukin (IL)-1α, IL-1β, IL-6 and tumor necrosis factor α] was shown to peak around 2h after pulmonary exposure to lipopolysaccharide in female C57BL/6J mice, while upregulation serum amyloid A genes showed their highest upregulation at 8-12h after exposure (Jeyaseelan et al., 2004).
Known Feedforward/Feedback loops influencing this KER
Some acute phase proteins (f. ex. C-reactive protein, serum amyloid A and complement components) have pro-inflammatory functions, including induction of inflammatory cytokines, chemotaxis and activation of immune cells. On the other hand, other acute phase proteins present anti-inflammatory functions (f. ex. Haptoglobin and fibrinogen) as antioxidative and tissue repair inducer (Gabay & Kushner, 1999).
Domain of Applicability
Acute phase response is present in vertebrate species (Cray, Zaias, & Altman, 2009). In addition, serum amyloid A, one of the major acute phase proteins, has been conserved in mammals throughout evolution and has been described in humans, mice, dogs, horses, among others (Uhlar & Whitehead, 1999).
References
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Poulsen, S. S., Saber, A. T., Williams, A., Andersen, O., Kobler, C., Atluri, R., Pozzebon, M. E., Mucelli, S. P., Simion, M., Rickerby, D., Mortensen, A., Jackson, P., Kyjovska, Z. O., Molhave, K., Jacobsen, N. R., Jensen, K. A., Yauk, C. L., Wallin, H., Halappanavar, S., & Vogel, U. (2015). MWCNTs of different physicochemical properties cause similar inflammatory responses, but differences in transcriptional and histological markers of fibrosis in mouse lungs. Toxicol Appl Pharmacol, 284(1), 16–32. https://doi.org/10.1016/j.taap.2014.12.011
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Saber, A. T., Bornholdt, J., Dybdahl, M., Sharma, A. K., Loft, S., Vogel, U., & Wallin, H. (2005). Tumor necrosis factor is not required for particle-induced genotoxicity and pulmonary inflammation. Arch Toxicol, 79(3), 177–182. https://doi.org/10.1007/s00204-004-0613-9
Saber, A. T., Halappanavar, S., Folkmann, J. K., Bornholdt, J., Boisen, A. M., Moller, P., Williams, A., Yauk, C., Vogel, U., Loft, S., & Wallin, H. (2009). Lack of acute phase response in the livers of mice exposed to diesel exhaust particles or carbon black by inhalation. Part Fibre Toxicol, 6, 12. https://doi.org/10.1186/1743-8977-6-12
Saber, A. T., Jacobsen, N. R., Mortensen, A., Szarek, J., Jackson, P., Madsen, A. M., Jensen, K. A., Koponen, I. K., Brunborg, G., Gutzkow, K. B., Vogel, U., & Wallin, H. (2012). Nanotitanium dioxide toxicity in mouse lung is reduced in sanding dust from paint. Part Fibre Toxicol, 9, 4. https://doi.org/10.1186/1743-8977-9-4
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