Abstract
Our earlier studies demonstrated slower age-related memory decline in IL-6-deficient than in control mice. Therefore, in the present study we evaluated the effect of IL-6 deficiency and aging on expression of p53, connected with accumulation of age-related cellular damages, in hippocampus of 4- and 24-month-old IL-6-deficient C57BL/6J (IL-6KO) and wild type control (WT) mice. The accumulation of p53 protein in hippocampus of aged IL-6KO mice was significantly lower than in aged WT ones, while p53 mRNA level was significantly higher in IL-6-deficient mice, what indicates that the effect was independent on p53 transcription. Presence of few apoptotic cells in hippocampal dentate gyrus and lack of changes in levels of pro-apoptotic Bax, antiapoptotic Bcl-2, as well as in p21 protein in aged animals of both genotypes, points to low transcriptional activity of p53, especially in aged WT mice. Because the amount of p53 protein did not correlate with the level of Mdm2 protein, its main negative regulator, other than Mdm2-dependent mechanism was involved in p53 build-up. Significantly higher mRNA levels of autophagy-associated genes: Pten, Tsc2, and Dram1 in IL-6KO mice, in conjunction with significantly lower amount of Bcl-2 protein in 4-month-old IL-6KO mice, suggests that lack of IL-6/STAT3/Bcl-2 signaling could account for better autophagy performance in these mice, preventing excessive accumulation of proteins. Taken together, attenuated p53 protein build-up, absence of enhanced apoptosis, and transcriptional up-regulation of autophagy-associated genes imply that IL-6 deficiency may protect hippocampus from age-related accumulation of cellular damages.
Highlights
Interleukin 6 (IL-6) is a small signaling glycoprotein with a diverse set of actions that depend on the target cell type
Aging was associated with down-regulation of Phosphatase and tensin homologue (Pten) mRNA expression, which was statistically significant in 24-month-old IL-6-deficient mice C57BL/6JIL-6-/-TMKopf (IL-6KO) mice in comparison with
Evaluation of Tuberos sclerosis 2 (Tsc2) mRNA expression within b Fig. 4 a Amount of glial fibrillary acidic protein (GFAP) in hippocampus of 4- and 24-month-old IL-6-deficient (IL-6KO) and wild type control (WT) mice was comparable in both young adult groups and insignificantly higher in both aged groups
Summary
Interleukin 6 (IL-6) is a small signaling glycoprotein with a diverse set of actions that depend on the target cell type. IL-6 exerts biological effects either via the membrane bound IL-6 receptor (classical signaling) or via the soluble form of IL-6 receptor (trans-signaling), and the latter one has been suggested to be of particular importance in the CNS (Erta et al 2012; Heinrich et al 2003; Spooren et al 2011). Both signaling pathways depend on the membrane bound gp130 subunits. In addition to activation of the STAT3 pathway, the RAS/ mitogen-activated protein kinase (MAPK), phosphatidylinositol-3 kinase (PI3 K) and insulin receptor substrate (IRS) pathways can be activated by the IL-6/ IL-6R/gp130 complex (Boulanger et al 2003; Erta et al 2012; Heinrich et al 2003)
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