TERMINAL DIFFERENTIATION OF HUMAN BONE-MARROW CELLS CAPABLE OF SPONTANEOUS AND HIGH-RATE IMMUNOGLOBULIN SECRETION - ROLE OF BONE-MARROW STROMAL CELLS AND INTERLEUKIN-6

Human bone marrow (BM) is a major site for in vivo immunoglobulin (Ig) formation. A subset of BM cells has been described which is capable of high-rate Ig secretion for 14 days in vitro without additional stimuli. Therefore, it provides a suitable model for analyzing the terminal B cell differentiation within the BM. The pleiotropic cytokine interleukin (IL) 6 was found to be essential for the further maturation of BM spontaneous Ig-secreting cells, as can be deduced from the following findings: (a) the addition of anti-IL-6 antibodies inhibited most of their Ig production; (b) when endogeneous IL 6 synthesis in the culture was restricted by using serum-free medium, the missing IgG secretion could be restored by the addition of exogenous IL 6; and (c) active IL 6 synthesis by BM cells in fetal calf serum-containing cultures was confirmed by direct quantitation (range 0.37-2.1 ng/ml). The presence of IL 6 during the first 3 days of culture was necessary for the induction of Ig secretion. Since neither the proliferation of these cells was elicited by IL 6 nor the inhibition of the DNA synthesis in these cultures prevented the IL 6-mediated Ig secretion, IL 6 must act on the BM Ig-secreting cells as a differentiation factor. The source of the endogenous IL 6 was, apparently, an adherent cell, since most of the IL 6 production was present in this cell fraction. In contrast, the nonadherent BM cell fraction contained all of the mature Ig-secreting cells even though it produced little, if any, IL 6; the combination of both populations completely restored Ig secretion. Finally, homogeneous populations of fibroblastic stromal cells derived from long-term BM cultures were totally efficient in inducing Ig secretion by purified BM CD38+ cells; this phenomenon was also demonstrated to be IL 6 mediated. Taken together, these findings appear to indicate that BM Ig-secreting cells are not terminally differentiated, suggesting that their final maturation could be mediated by the BM microenvironment via the paracrine production of IL 6.