The regulatory mechanisms that determine the course of an inflammation induced by an intraperitoneal injection of kaolin were investigated in Listeria-susceptible CBA and Listeria-resistant B10 mice. The magnitude of the granulocyte inflammatory response in the peritoneal cavity was high in B10 mice (area under the curve; AUC0-48 h: 210.9 x 10(6) granulocytes/mouse x h) and lower in CBA mice AUC0-48 h: 136.8 x 10(6) granulocytes/mouse x h), whereas the reverse was seen for the granulocyte response in the peripheral blood (AUC0-48 h: 30.5 and 80.7 x 10(6) granulocytes/mouse x h, respectively). With respect to the presence of humoral factors that affect the number of granulocytes in the circulation, sera of both mouse strains sampled 24 h after the kaolin injection had granulocytosis-inducing effect in CBA recipient mice and did not induce a response in the B10 recipient mice. This divergent sensitivity to serum factors inducing granulocytosis is consistent with the difference in the blood granulocyte response of B10 and CBA mice but does not explain the divergent inflammatory responses in the peritoneal cavity. Computer simulation showed that at least two factors must be taken into consideration to explain the differences in the inflammatory response, i.e., a factor regulating the release of granulocytes from the bone marrow and a factor governing the rate of granulocyte efflux from the site of inflammation.

Earlier investigations had indicated that the factor increasing monocytopoiesis (FIM), present in the serum of mice and rabbits during the onset of an inflammatory response, is released by cells of the inflammatory exudate. The present study was performed to determine which cells produce and secrete this factor and to establish the kinetics of its production and secretion. FIM was assayed in vivo by intravenous injection of samples into untreated mice and monitoring the course of the number of blood monocytes in the recipients. FIM was assayed in vitro by adding samples to cultures of the macrophage cell line PU5 and determining the rate of proliferation of the cells. The results show that only macrophages contain and synthesize FIM. This factor is secreted upon exposure to a phagocytic stimulus, and after the release of preformed FIM, macrophages secrete newly synthesized FIM. Granulocytes and lymphocytes neither contain nor secrete FIM. The characteristics of FIM derived from macrophages are in all aspects similar to those of FIM in serum. Macrophage-derived FIM is a protein with a molecular weight between 10 and 25 X 10(3), its activity is cell-lineage specific and dose dependent, and it stimulates monocyte production in the bone marrow. Macrophage-derived FIM is not identical to either CSF-1 or IL-1, and has no chemotactic activity. Taken together, the present results show that FIM occurring in serum during an inflammatory response originates from macrophages at the site of the inflammation. In this way the macrophages themselves regulate the supply of circulating blood monocytes that can migrate to the site of injury when needed.