The role of tumor necrosis factor α in the pathophysiology of human multiple myeloma:: therapeutic applications

In this study we demonstrate that tumor necrosis factor alpha (TNF alpha) triggers only modest proliferation, as well as p44/p42 mitogen-activated protein kinase (MAPK) and NF-kappaB activation, in MM.1S multiple myeloma (MM) cells. TNF alpha also activates NF-kappaB and markedly upregulates (fivefold) secretion of interleukin-6 (IL-6), a myeloma growth and survival factor, in bone marrow stromal cells (BMSCs). TNF alpha in both a dose and time dependent fashion induced expression of CD11a (LFA-1), CD54 (intercellular adhesion molecule-1, ICAM-1), CD106 (vascular cell adhesion molecule-1, VCAM-1), CD49d (very late activating antigen-4, VLA-4), and/or MUC-1 on MM cell lines; as well as CD106 (VCAM-1) and CD54 (ICAM-1) expression on BMSCs. This resulted in increased (2-4-fold) per cent specific binding of MM cells to BMSCs, with related IL-6 secretion. Importantly, the proteasome inhibitor PS-341 abrogated TNF alpha -induced NF-kappaB activation, induction of ICAM-1 or VCAM-1, and increased adhesion of MM cells to BMSCs. Agents which act to inhibit TNF alpha may therefore abrogate the paracrine growth and survival advantage conferred by MM cell adhesion in the BM microenvironment.