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Alteration of kinase-mediated signalings in murine peritoneal macrophages by aflatoxin B(1)
1Central Research Laboratories, Dong-Wha Pharm. Ind. Co. Ltd., Anyang-Dong Anyang City, Kyunggido, South Korea.
Abstract:
Aflatoxin B(1) (AFB(1)) is a potent hepatocarcinogen which is thought to exhibit an impairment of specific and non-specific immunity. Macrophages are responsible for non-specific immunity in host defense against tumors and microorganisms, and release a number of cytotoxic compounds, including nitric oxide (NO). We investigate whether the effect of AFB(1) on signal transduction is related to the decrease of NO production in murine peritoneal macrophages. When macrophages were stimulated with lipopolysaccharide (LPS) after AFB(1)-pretreatment, AFB1 decreased the NO production. The percentage of NO production in AFB(1)-pretreated macrophages was inversely increased by the addition of cholera toxin, phorbol 12-myrisate 13-acetate (PMA) and ionomycin. This suggests that AFB(1) affects the function of signaling constituents, including guanine nucleotide-binding protein (G protein), protein kinase C (PKC) and the calcium ion. AFB(1)-pretreatment significantly decreased PKC activity and tyrosine phosphorylation after LPS-stimulation. Taken together, these data propose that the inhibition of LPS-stimulated NO production by AFB(1) is related to the suppression of kinase-mediated intracellular signal transduction in murine peritoneal macrophages.
Insights
Aflatoxin B(1) exposure impairs macrophage nitric oxide (NO) production by disrupting intracellular signaling pathways. This study reveals AFB(1) suppresses key kinase activities essential for immune response.
Area of Science:
- Immunology
- Toxicology
- Cellular Biology
Background:
- Aflatoxin B(1) (AFB(1)) is a known hepatocarcinogen.
- AFB(1) is suspected to impair both specific and non-specific immunity.
- Macrophages are crucial for non-specific immunity, producing nitric oxide (NO) for host defense.
Purpose of the Study:
- To investigate the link between AFB(1)'s effect on signal transduction and reduced NO production in murine macrophages.
- To elucidate the specific signaling pathways affected by AFB(1) in macrophages.
Main Methods:
- Murine peritoneal macrophages were pretreated with AFB(1).
- Macrophages were stimulated with lipopolysaccharide (LPS) with or without AFB(1).
- Nitric oxide (NO) production, protein kinase C (PKC) activity, and tyrosine phosphorylation were measured.
Main Results:
- AFB(1) pretreatment significantly decreased NO production in LPS-stimulated macrophages.
- The addition of cholera toxin, phorbol 12-myristate 13-acetate (PMA), and ionomycin partially restored NO production, suggesting AFB(1) affects G protein, PKC, and calcium ion signaling.
- AFB(1) significantly reduced PKC activity and tyrosine phosphorylation following LPS stimulation.
Conclusions:
- AFB(1) inhibits LPS-stimulated NO production in murine peritoneal macrophages.
- This inhibition is linked to the suppression of kinase-mediated intracellular signal transduction pathways, including PKC and tyrosine phosphorylation.
