Interleukin-1β expression in murine J774A.1 macrophages exposed to platinum compounds: The role of p38 and ERK 1/2 mitogen-activated protein kinases

Abstract Although skin and respiratory sensitizing properties of platinum compounds have been proved in humans and mice, little is known about signal transduction pathways leading to cytokine production in the induction phase. It is generally assumed that induction of skin sensitization, but not skin irritation, is associated with a rapid increase in the IL-1β mRNA expression. In this study, IL-1β expression and a role of mitogen-activated protein kinases (MAPKs) in this process were investigated in murine macrophages J774A.1 exposed to four platinum compounds. Potassium tetrachloroplatinate (K 2 PtCl 4 ; TCPP), ammonium tetrachloroplatinate ((NH 4 ) 2 PtCl 4 ; TCPA), ammonium hexachloroplatinate ((NH 4 ) 2 PtCl 6 ; HCPA) showed a very similar range of cytotoxic concentrations (IC 50 values: 238 μM ± 30; 269 μM ± 39 and 245 μM ± 31, respectively) as assessed in the 24-h MTT reduction test. Cytotoxicity of cis -diammineplatinum dichloride (cisplatin) was considerably higher (IC 50 of 23 μM ± 4). While increased expression of IL-1β mRNA was observed in the macrophages exposed to each test compound, IL-1β protein production was detected in cell lysates after treatment with TCPP, TCPA and HCPA for 24 h (concentration range of 150–350 μM) as well as for 2 h (450–650 μM). The treatment with each compound resulted in the phosphorylation of both p38 MAPK and ERK 1/2 (p44/42). Blocking the activation of p38 MAPK as well as ERK 1/2 with specific inhibitors (SB203580 and U0126, respectively) down-regulated the IL-1β expression. Interestingly, the skin irritant sodium dodecyl sulfate did not trigger phosphorylation of these kinases, nor induced IL-1β production. These data suggest that p38 MAPK and ERK 1/2 play an important role in induction of IL-1β expression in J774A.1 macrophages exposed to test platinum compounds.