An intrinsic thyrotropin-mediated pathway of TNF-alpha production by bone marrow cells

Recent studies have identified a role for thyroid-stimulating hormone (TSH; ie, thyrotropin) as an inductive signal for tumor necrosis factor-alpha (TNF-alpha) secretion by bone marrow (BM) cells, although the features of that activation pathway have not been defined. Using intracellular TSH staining and enzyme-linked immunoassay for detection of secreted TSH, we demonstrate that TSH synthesis in BM cells occurs within CD45(+) (leukocyte common antigen) hematopoietic cells and that the majority of that activity resides in a component of CD11b(+) BM cells that are not mature T cells, B cells, or Thy-1(+) cells in the BM. Conversely, TSH-responsive BM cells defined by expression of TSH receptor (TSHR) using flow cytometry were selectively associated with a nonerythroid CD11b(-) lymphocyte precursor population. In vitro culture of magnetic-activated cell sorted CD11b(-) and CD11b(+) cells with titrated amounts of purified TSH resulted in significantly higher levels of TNF-alpha secretion from CD11b(-) BM cells compared to non-TSH-treated cells, with no appreciable change in TNF-alpha production from CD11b(+) cells. These findings are the first to demonstrate TSH production by BM hematopoietic cells, and they demonstrate that TSH may be involved in the regulation of TNF-alpha by CD11b(-) BM cells. They also indicate that TSH-mediated regulation of TNF-alpha secretion within the BM most likely operates through an intrinsic network of TSH production and use between different types of BM cells, and they suggest that local TSH may be an important homeostatic regulator of hematopoiesis mediated by TNF-alpha.