title: Systemic drugs inducing non-immediate cutaneous adverse reactions and contact sensitizers evoke similar responses in THP-1 cells.
abstract: Contact sensitizers induce phenotypic and functional changes in dendritic cells (DC) that enhance their antigen-presenting capacity and, ultimately, modulate the T cell response. To evaluate if there is a similar effect of drugs causing T-cell-mediated cutaneous adverse drug reactions (CADR), we studied the in vitro effect of drugs on THP-1 cells, a cell line widely used to evaluate the early molecular and cellular events triggered by contact sensitizers. The effect of allopurinol, oxypurinol, ampicillin, amoxicillin, carbamazepine and sodium valproate, at EC30 concentrations, was evaluated on p38 MAPK activation, by Western Blot, and on the expression of genes coding for DC maturation markers, pro-inflammatory cytokine/chemokines and hemeoxygenase 1 (HMOX1), by real-time RT-PCR. Results were compared with lipopolysaccharide (LPS), a DC maturation stimulus, and the strong contact sensitizer, 1-fluoro-2,4-dinitrobenzene (DNFB). All drugs studied significantly upregulated HMOX1 gene transcription and all, except the anticonvulsants, also upregulated IL8. Allopurinol and oxypurinol showed the most intense effect, in a magnitude similar to DNFB and superior to betalactams. Transcription of CD40, IL12B and CXCL10 genes by drugs was more irregular. Moreover, like DNFB, all drugs activated p38 MAPK, although significantly only for oxypurinol. Like contact sensitizers, drugs that cause non-immediate CADR activate THP-1 cells in vitro, using different signalling pathways and affecting gene transcription with an intensity that may reflect the frequency and severity of the CADR they cause. Direct activation of antigen-presenting DC by systemic drugs may be an important early step in the pathophysiology of non-immediate CADR.
authors.affiliation: Department of Dermatology, University Hospital and Faculty of Medicine, University of Coimbra, 3000-075, Coimbra, Portugal.
authors.forename: Margarida
authors.initials: M
authors.lastname: Gonçalo
authors.forename: João
authors.initials: J
authors.lastname: Martins
authors.forename: Ana
authors.initials: A
authors.lastname: Silva
authors.forename: Bruno
authors.initials: B
authors.lastname: Neves
authors.forename: Américo
authors.initials: A
authors.lastname: Figueiredo
authors.forename: Teresa
authors.initials: T
authors.lastname: Cruz
authors.forename: Celeste
authors.initials: C
authors.lastname: Lopes
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000494:pharmacology*; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D004139:Dinitrofluorobenzene / Q000494:pharmacology / Q000633:toxicity; D004342:Drug Hypersensitivity / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006241:Haptens / Q000009:adverse effects / Q000494:pharmacology*; D051547:Heme Oxygenase-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007509:Irritants / Q000494:pharmacology / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology / Q000633:toxicity; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009000:Monocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D000927:Anticonvulsants; D015415:Biomarkers; D016207:Cytokines; D004791:Enzyme Inhibitors; D006241:Haptens; D007509:Irritants; D008070:Lipopolysaccharides; C433788:lipopolysaccharide, E. coli O26-B6; D004139:Dinitrofluorobenzene; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases
keywords: HMOX1; IL8; THP-1 cells; allopurinol; amoxicillin; carbamazepine; drug allergy; drug hypersensitivity; non-immediate drug eruptions; oxypurinol