Cascade regulation of cytokine production in granulopoiesis.

Injection of IL-3 producing T cells (STIL-3) resulted in a granulocytosis in the syngeneic mice. A high IL-3 activity was detected in the culture supernatant of the spleen cells of these mice, but only a low activity was detectable in the bone marrow cell-conditioned medium. There was no significant difference in the distribution of the STIL-3 cells between the spleen and the bone marrow of the mice injected with the STIL-3 cells. Two possibilities have been envisaged from these observations; i) IL-3 induces production of granulocyte stimulating cytokines (CSFs) from hemopoietic cells hence resulting in the granulocytosis in the STIL-3 injected mice, ii) an inhibitor of IL-3 is produced in response to an excess stimuli with IL-3 in the bone marrow. We found that IL-3 induced a production of IL-6, G- and GM-CSF from bone marrow cells. In contrast, stimulation of the bone marrow cells with an excess level of IL-3 resulted in a production of a heat-labile activity (NIL-3) antagonistic to IL-3. Furthermore, stimulation of bone marrow cells with IL-6, G- or GM-CSF did not induce the production of IL-3, indicating a hierarchical regulation of the cytokine production. These observations have provided positive evidences to the above mentioned 2 possibilities, and indicate the existence of a positive feedback mechanism in the IL-3-induced granulocytosis, as well as the presence of a negative feedback mechanism for the homeostatic regulation of the granulopoiesis.