Abstract
Growth expansion of monoclonal plasma cells (myeloma cells) in the bone marrow (BM) is triggered by increase in serum interleukin-6 (IL-6). Indeed, high levels of IL-6 have been found in the serum of patients with progressive multiple myeloma (MM), and a reduction of the tumor cell mass has been reported by inhibition of myeloma cell proliferation with anti-IL-6 antibodies. On the other hand, IL-6 is considered to increase physiologically in its serum level along with age, and the age-related increase in serum IL-6 could be related to the age-dependent diseases such as rheumatoid arthritis, atherosclerosis, Alzheimer’s disease and B cell malignancies including myelomas. Recent reports also show that the age-associated decline in the serum level of an adrenal sex hormone, dehydroepiandrosterone sulfate (DHEA-S), is closely related to the increase in serum IL-6. Here, we show that DHEA-S is decreased significantly more than that by physiological decline with age in overt myeloma, but not in other lymphoid malignancies such as malignant lymphoma or macroglobulinemia. DHEA-S as well as DHEA suppressed IL-6 production from a BM stromal cell line, KM-102, and bone marrow mononuclear cells from patients with MM. Furthermore, DHEA inhibited in vitro growth of the U-266 cell line and primary myeloma cells from the patients, and also in vivo growth of U-266 cells intraperitoneally implanted in SCID-hIL6 transgenic mice. DHEA upregulated the expression of peroxisome proliferator activated receptor (PPAR)β and IκBα gene in myeloma cells and BM stromal cells, which could explain the suppressive effect of DHEA on IL-6 production through the downregulation of NF-κB activity. PPAR agonists such as troglitazone, carbacyclin and WY14643, also inhibited the growth of myeloma cell lines and primary myeloma cells. Therefore, these findings suggest that DHEA has a capability of inhibiting the growth of myeloma cells and IL-6 production of bone marrow mononuclear cells through activation of PPAR and/or suppression of NFκB activity, and inversely a decreased level of DHEA and DHEA-S could upregulate IL-6 activity, which could be responsible for progression of myeloma cells.
Age-related defects in autophagy alter the secretion of paracrine factors from bone marrow mononuclear cells
