The MDM2 inhibitor Nutlin-3 attenuates streptozotocin-induced diabetes mellitus and increases serum level of IL-12p40
- 550 Downloads
Besides its well-established oncosuppressor activity, a key function of p53 in regulating metabolic pathways has been recently identified. Nevertheless, the role of p53 with respect to diabetes mellitus (DM) appears highly controversial. To address this issue, we have used the cis-imidazoline compound Nutlin-3, an inhibitor of MDM2/p53 interaction, which represents a potent and selective non-genotoxic activator of the p53 pathway both in in vivo and in vitro experimental settings. Experimental DM was induced by intraperitoneal injections of low concentrations of streptozotocin (STZ) in C57BL/6N mice (n = 20). A group of control vehicle-injected mice (n = 10) and of STZ-treated mice (n = 10) was co-injected with Nutlin-3. Mice co-injected with STZ + Nutlin-3 exhibited attenuated features of DM with respect to animals treated with STZ alone. Indeed, STZ + Nutlin-3-treated mice were characterized by significantly (p < 0.05) lower levels of hyperglycemia, reduced weight loss, and increased spleen weight. In addition, STZ alone promoted a marked decrease in the levels of several circulating cytokines, including interleukin-12 (IL-12)p40. On the other hand, co-injection of STZ + Nutlin-3 significantly (p < 0.01) counteracted IL-12p40 down-modulation. In vitro experiments performed on the RAW264.7 macrophagic cell line model, used as cellular source of IL-12p40, demonstrated that Nutlin-3 treatment increased IL-12p40 release, strongly suggesting a direct effect of Nutlin-3 on the immune system. Overall, these data demonstrate that systemic administration of Nutlin-3 ameliorates the severity of STZ-induced DM and increases the levels of circulating IL-12p40.
KeywordsNutlin-3 Diabetes mellitus Serum cytokines IL-12p40
This work was supported by the grants from the Italian Ministry of Health to the IRCCS “Burlo Garofolo” of Trieste and by Italian Association for Cancer Research (AIRC) grant (IG 11465 to G. Zauli) and FIRB-MIUR grant (to G. Zauli). Chiara Agnoletto has been supported by a “Consorzio Spinner PhD Program.” We are extremely grateful to Riccardo Candido, M.D., PhD (Diabetological Centre ASS1 Trieste, Trieste, Italy), for the revision of the manuscript.
Conflict of interest
The authors have no conflicts of interest.
- 2.Cunha DA, Igoillo-Esteve M, Gurzov EN, Germano CM, Naamane N, Marhfour I, Fukaya M, Vanderwinden JM, Gysemans C, Mathieu C, Marselli L, Marchetti P, Harding HP, Ron D, Eizirik DL, Cnop M (2012) Death protein 5 and p53-upregulated modulator of apoptosis mediate the endoplasmic reticulum stress-mitochondrial dialog triggering lipotoxic rodent and human β-cell apoptosis. Diabetes 61:2763–2775PubMedCrossRefGoogle Scholar
- 6.Franck D, Tracy L, Armata HL, Delaney CL, Jung DY, Ko HJ, Ong H, Kim JK, Scrable HK (2012) Glucose tolerance in mice is linked to the dose of the p53 transactivation domain. Endocr Res (Epub ahead of print)Google Scholar
- 7.Burgdorf KS, Grarup N, Justesen JM, Harder MN, Witte DR, Jørgensen T, Sandbæk A, Lauritzen T, Madsbad S, Hansen T (2011) DIAGRAM Consortium, Pedersen O. Studies of the association of Arg72Pro of tumor suppressor protein p53 with type 2 diabetes in a combined analysis of 55,521 Europeans. PLoS ONE 6:e15813PubMedCrossRefGoogle Scholar
- 8.Bonfigli AR, Sirolla C, Testa R, Cucchi M, Spazzafumo L, Salvioli S, Ceriello A, Olivieri F, Festa R, Procopio AD, Brandoni G, Boemi M, Marra M, Franceschi C (2012) The p53 codon 72 (Arg72Pro) polymorphism is associated with the degree of insulin resistance in type 2 diabetic subjects: a cross-sectional study. Acta Diabetol (Epub ahead of print)Google Scholar
- 22.Zauli G, La Placa M, Vignoli M, Re MC, Gibellini D, Furlini G, Milani D, Marchisio M, Mazzoni M, Capitani S (1995) An autocrine loop of HIV type-1 Tat protein responsible for the improved survival/proliferation capacity of permanently tat-transfected cells and required for optimal HIV-1 LTR transactivating activity. J Acquir Immune Defic Syndr Hum Retrovirol 10:306–316PubMedCrossRefGoogle Scholar