title: A toxicokinetic study of nickel-induced immunosuppression in rats.
abstract: The aim of the present study was to investigate dose- and time-dependent effects of NiCl2 on T-lymphocyte and macrophage-derived cytokine production in rats. Moreover we have determined the concentrations of nickel in the plasma that are required to elicit alterations in T-lymphocyte and macrophage function. NiCl2 suppressed T-lymphocyte proliferation and Th1 (IFN-gamma) and Th2 (IL-10) cytokine production in a dose- and time-dependent fashion. In addition, NiCl2 inhibited production of the pro-inflammatory cytokine TNF-alpha and increased production of the anti-inflammatory cytokine IL-10 from lipopolysaccharide (LPS) stimulated cultures. We have determined that the minimal plasma concentrations of nickel required to provoke immunosuppression are in the range 209-585 ng/mL. In the time-course study NiCl2 (3.3 mg/kg) provoked immunological changes that were maximal 1 h following administration, and some of these changes persisted for up to 24 h post administration. Overall these data clearly demonstrate that NiCl2 suppresses T-cell function and promotes an immunosuppressive macrophage phenotype in rats. This study also indicates that measuring T-cell proliferation is as sensitive a marker of NiCl2-induced immunotoxicity as measuring T-cell or macrophage cytokine production. Co-measurement of circulating nickel concentrations and immune parameters yields valuable information with regard to the potency of nickel to alter immune function in vivo. These data also suggest that quite a large quantity of nickel needs to reach the systemic circulation before any adverse effects on immune function are observed.
authors.affiliation: Department of Pharmacology, National University of Ireland, Galway, Ireland. andrew.harkin@nuigalway.ie
authors.forename: Andrew
authors.initials: A
authors.lastname: Harkin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hynes
authors.forename: Eoghan
authors.initials: E
authors.lastname: Masterson
authors.forename: John P
authors.initials: JP
authors.lastname: Kelly
authors.forename: James M
authors.initials: JM
authors.lastname: O'Donnell
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Connor
mesh_terms: D000818:Animals; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D007958:Leukocyte Count; D008213:Lymphocyte Activation / Q000187:drug effects; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D009532:Nickel / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D003208:Concanavalin A; D016753:Interleukin-10; C022838:nickel chloride; D009532:Nickel; D007371:Interferon-gamma