Betalactam antibiotics affect human dendritic cells maturation through MAPK/NF-kB systems. Role in allergic reactions to drugs

• Published in: Toxicology and applied pharmacology 2015-11, Vol.288 (3), p.289-299
• Main Authors: Lopez, Soledad, Gomez, Enrique, Torres, Maria J., Pozo, David, Fernandez, Tahia D., Ariza, Adriana, Sanz, Maria L., Blanca, Miguel, Mayorga, Cristobalina
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Adult; ALLERGY; Amoxicillin; Amoxicillin - pharmacology; Anti-Bacterial Agents - pharmacology; ANTIBIOTICS; beta-Lactams - pharmacology; Cell Differentiation - drug effects; Delayed-type hypersensitivity; DENDRITES; Dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - metabolism; Down-Regulation; Drug Hypersensitivity - metabolism; Endocytosis - drug effects; Female; FLUORESCENCE; HISTOCOMPATIBILITY COMPLEX; Humans; LIPOPOLYSACCHARIDES; LYMPHOCYTES; Male; MAP Kinase Signaling System; Middle Aged; MONOCYTES; Monocytes - drug effects; Monocytes - metabolism; NF-kappa B - genetics; NF-kappa B - metabolism; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; PHOSPHORUS 38; Phosphorylation; PHOSPHOTRANSFERASES; RECEPTORS; Signaling pathway; T lymphocytes; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Up-Regulation
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/j.taap.2015.08.001

The mechanisms leading to drug allergy in predisposed patients, especially those related to T-cell-mediated drug hypersensitivity, are not well understood. A key event in allergic reactions to drugs is the maturation process undergone by dendritic cells (DCs). Although amoxicillin (AX) has been reported to interact and maturate DCs from patients with AX-induced delayed-type hypersensitivity, the cell signaling pathways related to AX-mediated DC maturation have not been elucidated. We sought to determine the role of the MAPK and NF-κΒ pathways on AX-induced DC maturation and functional status. For that purpose, in monocyte-derived-DCs from AX-delayed allergic patients and tolerant subjects, we analyzed the activation pattern of p38MAPK, JNK, and ERK signaling and the NF-κB, maturation markers as well as endocytosis and allostimulatory capacities driven by AX-stimulated-DCs. Our data reveal that AX induces an increase in the phosphorylation levels of the three MAPKsand activated NF-κB in DCs from allergic patients. Moreover, the inhibition of these pathways prevents the up-regulation of surface molecules induced by AX. Additionally, we observed that the allostimulatory capacity and the endocytosis down-regulation in AX-stimulated-DCs from allergic patients depend on JNK and NF-κB activities. Taken together, our data shed light for the first time on the main signaling pathways involved in DC maturation from AX-delayed allergic patient. •The cell signaling pathways related to drug-mediated DC maturation were tested.•Amoxicillin induces activation of MAPK and NF-κB in DCs from allergic patients.•The inhibition of these pathways prevents the up-regulation of DC surface molecules.•Their allostimulatory and endocytosis capacities depend on JNK and NF-κB activities.•The low involvement of p38-MAPK could be the cause of an incomplete DC maturation.