Aims/hypothesis. Monocyte chemoattractant protein-1 (MCP-1) attracts monocytes and T lymphocytes, and could thus contribute to mononuclear
cell infiltration in Type I (insulin-dependent) diabetes mellitus. Cytokines induce MCP-1 mRNA expression in pancreatic rat
beta cells. To investigate this issue, we analysed the signal transduction for IL-1
β-induced MCP-1 expression in rat beta cells and in vitro MCP-1 mRNA expression and protein release by human islets as well
as in vivo islet MCP-1 mRNA expression in prediabetic non-obese diabetic mice.
Methods. Fluorescence-activated cell sorting-purified rat beta cells were cultured for 6 h with IL-1
β (30 U/ml) or MAPK inhibitors or both. Human islets were cultured for 6–72 h with the cytokines IL-1
β, IFN-
γ or the inducible nitric oxide synthase (iNOS) inhibitor
N
G-methyl-
l-arginine or both. We measured MCP-1 mRNA by RT-PCR and protein by ELISA. The MCP-1 mRNA expression in islets from male and
female non-obese diabetic mice (2–12 weeks of age) was measured by real time reverse transcription-polymerase chain reaction
(RT-PCR).
Results. Interleukin-1
β induced MCP-1 mRNA expression in rat beta cells, with a maximum induction after 6 h. A combination of p38 and ERK1/2 inhibitors
decreased MCP-1 expression by 70 %. IL-1
β induced both MCP-1 mRNA expression and a threefold increase in medium MCP-1 protein accumulation in human islet cells. This
effect was not prevented by iNOS blockers. In vivo there was an age-related increase in MCP-1 mRNA expression in islets from
male and female non-obese diabetic mice, reaching a peak at 8 weeks.
Conclusion/interpretation. In rat and human islet cells MCP-1 mRNA is induced by IL-1
β. Both ERK1/2 and p38 MAPK, but not nitric oxide, contribute to MCP-1 expression. In non-obese diabetic mice MCP-1 mRNA expression
increases with age, peaking at the early phases of insulitis. The production of MCP-1 by pancreatic beta cells could contribute
to the recruitment of mononuclear cells into pancreatic islets in early Type I diabetes. [Diabetologia (2001) 44: 325–332]
Keywords Beta cell - MCP-1 - interleukin-1 - nitric oxide - diabetes mellitus - NOD mice - pancreatic islets - interferon-γ - human islets - polymerase chain reaction.
Received: 5 September 2000 and in revised form: 18 October 2000