Terminal differentiation of human bone marrow cells capable of spontaneous and high‐rate immunoglobulin secretion: Role of bone marrow stromal cells and interleukin 6

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Abstract
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 endogenous IL6 synthesis in the culture was restricted by using serum-free medium, the missing IgG secretion could be restored by the addition of exogenous IL6; and (c) active IL6 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 IL6 nor the inhibition of the DNA synthesis in these cultures prevented the IL6-mediated Ig secretion, IL6 must act on the BM Ig-secreting cells as a differentiation factor. The source of the endogenous IL6 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, IL6; 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 IL6 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 IL6.