Involvement of the proteasome in IL-1β induced suppression of islets of Langerhans in the rat

Abstract

The cytokine IL-1β suppresses rodent islets of Langerhans in vitro. Presently we used inhibitors of the proteasome to investigate if these compounds could counteract the suppressive effects of the cytokine. Thus, isolated rat islets were cultured and pre-treated with proteasome inhibitors and subsequently exposed for 48 h to 25 U/ml human IL-1beta. After this period functional tests were carried out. The rate of glucose oxidation (pmol/10 islets x 90 min) was suppressed by IL-1β (115 ± 17 vs. control 380 ±57). Pre-treatment with 10 μM of the proteasome inhibitor MG115 (N-carbobenzoxyl-leu-leu-norvalinal) and 100 μM of the calpain inhibitor norLEU (N-acetyl-leu-leu-norleucinal; known to affect proteasome activity) counteracted the suppressive effects (253 ± 17 and 262 ± 10 respectively). The calpain inhibitor alIMET (N-acetyl-leu-leu-methional) had no effect. MG115 (10 μM) and norLEU (100 μM) blocked nitric oxide formation induced by IL-1β, while alIMET was without effect. We also investigated if IL-1β could influence the expression of two inducible proteasome subunits, namely LMP2 and LMP7, and found that the cytokine increased the mRNA expression of the proteasome subunit LMP2 in islets, and that the proteasome inhibitor MG115 prevented this increase. In conclusion our study shows that IL-1β increases the transcription of the proteasome subunit LMP2, and that the proteasome is involved in IL-1β induced suppression of islet function. Moreover, the observation that inhibitors of the proteasome protect islets against IL-1β induced inhibition of glucose metabolism, suggests that these compounds might be worthwile to explore in future therapies against the development of type 1 diabetes.