Tenascin (TNC) is a gene thought to play a role in the binding of receptors and syndecan binding. Syndecans are signal transmembrane proteins that act as co receptors, specifically for G protein-couples receptors. Tenascin-C modifies syndecans in the extracellular matrix. The TNC-C gene is involved in synaptic plasticity and neuron regeneration, guiding migrating axons and neurons in development. The protein also contains ligands for various integrins such as alpha-8/beta-1 and alpha-9/beta-1. It is a hexameric protein that is available in embryonic development but basically missing from adult tissue. High TNC levels have been observed in renal transplant vasculopathy. In addition TNC has been shown to induce IL-17 production which is a major player in graft rejection. Bortezomib (PS-341), a selective 26S proteasome inhibitor, has been used to treat antibody mediated rejection (AMR) among allograft recipients. The efficacy of Bortezomib treatment of AMR has been reported with both pure AMR and with mixed features of T cell mediated rejection (TCMR) and AMR. While the effect of Bortezomib is largely attributed to its effects on plasma cells (PCs), the 26S proteasome is distributed in cells other than PCs, which raises the possibility that additional signaling pathways may be impacted by Bortezomib. In the current study, we investigated the impact of PS-341(Bortezomib) treatment on TNC mRNA levels in PBMNC.

Methods: Human peripheral blood mononuclear cells (PMBCs) were isolated from normal healthy volunteers and treated with Bortezomib or vehicle control. cDNA microarray hybridization using a 42K genes slide array (Stanford University) was performed on RNA isolated from treated PMBCs. Array normalization and analysis were performed using TIGR software. Pathways were analyzed using Onto-Express. Microarray results were validated with Real-Time PCR. The protein expression levels were determined by western blot analysis.

Results: In Bortezomib treated PBMNC, Tenascin C mRNA levels were significantly decreased by 60% (p<0.05), and TNC protein levels were decreased.

Conclusions:Our findings point to significant effects of Bortezomib on TNC levels and suggest a novel pathway that can be regulated by 26S proteasome inhibition.

CITATION INFORMATION: Bradley E, Moussa O, Twombley K. Bortezomib Impacts Tenascin mRNA in PBMNCs. Am J Transplant. 2016;16 (suppl 3).

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