F EEDBACK REGU LATION OF COLONYSTIMULATING FACTOR PRODUCTION

The production of colony-stimulating factors (CSF) is delicately controlled through a complex network of humoral and environmental factors. We have studied some of the mechanisms which regulate the production of CSF as compared to general protein synthesis in the lung tissue ill vitro. When lung tissue from mice was cultured for various times in serum free medium, the first detectable level of CSF activity in the lung conditioned medium (LCM) appeared 6 hr after initiation of the culture, continued to rise until 24 hr, and then levelled off for several days. Under similar conditions protein synthesis did not level off, but continuously rose after 24 hr. When the lung tissue which had been cultured previously for 6,24, or 4X hr was recultured in fresh tissue culture medium, de IIOVO synthesis of CSF occurred as judged by CSF synthesis inhibition and stimulation studies. The amount of new CSF synthesized by these tissues decreased as the initial culturing period increased from 6 to 4X hr. There was also a decrease in the amount of total protein synthesis and release in the secondary lung cultures as a function of the initial culturing period. Endotoxin stimulation of 24 or 4X hrcultured lung tissues (plateau phase tissue) resulted in de IIOVO synthesis of CSF by these tissues. However, when fresh lung tissue was cultured in 24 or 4X hr LCM, no new CSF was produced by the fresh tissues, while under similar conditions, protein synthesis by these tissues was significant as judged by double-labelling experiments. On the other hand, n hr LCM was able to support both CSF production and protein synthesis by fresh lung tissues. The results suggest at least two distinct regulatory systems controlling CSF production by the lung ill vitro: 1- Aging which is responsible for general and nonspecific decrease in the rate of protein synthesis and CSF production in this system, and 2-Feedback regulation of CSF production by the level of CSF which is formed in the LCM.