Selective induction of type 2 cytokines following topical exposure of mice to platinum salts.
Repeated topical exposure of BALB/c strain mice to organic chemical respiratory allergens, such as trimellitic anhydride (TMA), or contact allergens such as 2,4-dinitrochlorobenzene (DNCB), provokes characteristic cytokine secretion profiles consistent with the divergent activation of discrete T cell subpopulations. Under such conditions, lymph node cells (LNC) isolated from animals exposed to TMA elaborated comparatively large amounts of the type 2 cytokines interleukin 10 (IL-10) and mitogen-inducible interleukin 4 (IL-4), but only low levels of the type 1 product interferon gamma (IFN-gamma). In contrast, DNCB-activated LNC displayed the converse (type 1) cytokine secretion profile. We have now examined cytokine production induced by topical application to mice of respiratory sensitizing platinum salts; ammonium tetrachloroplatinite II, ammonium hexachloroplatinate IV and cis-dichlorodiammine platinum II. Metal salts were dissolved in dimethyl sulfoxide (DMSO). Cytokine secretion profiles were compared with those elicited following concurrent exposure to TMA or DNCB or to the vehicle acetone:olive oil (AOO) alone. All three platinum salts and TMA stimulated vigorous IL-4 and IL-10 production compared with DNCB-activated LNC; vehicle-stimulated LNC failed to elaborate detectable levels of either cytokine. However, DNCB and the DMSO vehicle provoked substantial IFN-gamma expression, whereas exposure to AOO vehicle resulted in a considerably weaker IFN-gamma response. Levels of this cytokine induced by treatment with respiratory allergens were, in the majority of cases, substantially lower than those observed with the relevant vehicle. Indeed, an inverse dose-response relationship for IFN-gamma expression was exhibited by all three platinum salts, suggestive of the elaboration by platinum salt activated LNC of an inhibitory factor or factors for IFN-gamma. These data suggest that it may be possible to identify those metal salts with respiratory sensitizing potential as a function of induced type 2 cytokine secretion patterns.
Dearman
R J
RJ
Zeneca Central Toxicology Laboratory, Macclesfield, Cheshire, UK.
Basketter
D A
DA
Kimber
I
I
D000287:Administration, Topical; D000485:Allergens; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity; D002469:Cell Separation; D002712:Chlorides / Q000008:administration & dosage / Q000633:toxicity; D002945:Cisplatin / Q000008:administration & dosage / Q000633:toxicity; D016207:Cytokines / Q000032:analysis / Q000096:biosynthesis*; D004137:Dinitrochlorobenzene; D004797:Enzyme-Linked Immunosorbent Assay; D007371:Interferon-gamma / Q000032:analysis / Q000096:biosynthesis; D016753:Interleukin-10 / Q000032:analysis / Q000096:biosynthesis; D015847:Interleukin-4 / Q000032:analysis / Q000096:biosynthesis; D007509:Irritants; D008198:Lymph Nodes / Q000187:drug effects* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D010796:Phthalic Anhydrides; D017671:Platinum Compounds / Q000008:administration & dosage / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage / Q000633:toxicity
D000485:Allergens; D000970:Antineoplastic Agents; D002712:Chlorides; D016207:Cytokines; D004137:Dinitrochlorobenzene; D007509:Irritants; D010796:Phthalic Anhydrides; D017671:Platinum Compounds; D011838:Radiation-Sensitizing Agents; D016753:Interleukin-10; C036919:tetrachloroplatinate; C018453:ammonium hexachloroplatinate; D015847:Interleukin-4; C015559:trimellitic anhydride; D007371:Interferon-gamma; D002945:Cisplatin