Chemotherapy Treatment Induces An Interleukin-6 Deficit In The Bone Marrow Microenvironment

Bone marrow stromal cells (BMSC) are a critical component of the microenvironment that supports hematopoiesis, and hematopoietic recovery following bone marrow transplantation. Aggressive chemotherapy not only affects tumor cells, but also influences structural and functional components of the microenvironment, including BMSC and osteoblasts. Successful stem cell or bone marrow transplantation following immuno-suppressive or myeloablative chemotherapy is dependent on the ability of BMSC, and other cellular components of the microenvironment, to maintain their functionality. This includes secretion of soluble factors and expression of cellular adhesion molecules that are critical for the survival, proliferation, and differentiation of immature progenitor cells. In the current study, we have investigated the effects of chemotherapy treatment on BMSC and human osteoblast (HOB) expression of Interleukin-6 (IL-6). IL-6 is a pleiotrophic cytokine which has diverse effects on hematopoietic cell development. The treatment of BMSC or HOB with Melphalan or VP-16, which are clinically relevant drugs used in pre-transplant regimens, led to decreased IL-6 protein expression. This decrease in IL-6 protein is unique to Melphalan, as treatment with other chemotherapeutic agents does not result in a similar decrease in IL-6 protein. We have also observed a decrease in gp130, the transmembrane protein necessary for IL-6 signaling, in response to Melphalan treatment, but not VP-16 treatment. Additionally, pre-treatment of BMSC and HOB with Z-VAD-FMK or Leupeptin, a broad range caspase inhibitor and lysosomal inhibitor respectively, prior to chemotherapy treatment was not able to blunt the decrease in IL-6 protein detected in cell supernatants. These data suggest chemotherapy is not enhancing the degradation of IL-6 protein through caspase or lysosomal mediated mechanisms, but rather blunting the overall expression of IL-6. Melphalan treatment is also able to decrease IL-6 mRNA and further investigation is necessary to determine the mechanism by which chemotherapy affects transcription of IL-6. Collectively, these observations suggest that chemotherapy treatment induced alteration of bone marrow microenvironment function, which results in decreased or defective hematopoietic support of human embryonic stem cells and early progenitor cells may result, in part, from an IL-6 deficit. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3961.