Molecular mechanisms regulating TNF-α production by tumor-associated macrophages

The molecular mechanisms that regulate the production and/or functional activity of intratumoral tumor necrosis factor-α (TNF-α) remain poorly defined. To begin to address this issue we have examined the level of TNF-α mRNA and protein produced by macrophages present within immunogenic Fsa-R and non-immunogenic Fsa-N tumors grown in syngeneic Lpsd C3H/HeJ and Lpsn C3H/HeN mice. The results obtained indicate that macrophages isolated from tumors grown in Lpsd C3H/HeJ mice express 5–10-fold less TNF-α than equivalent cells present in tumors grown in Lpsn C3H/HeN mice. These data suggest that the mechanisms that operate within the tumor microenvironment to induce the production of TNF-α act, at least in part, via the same signal transduction pathway that is defective in Lpsd C3H/HeJ mice. Interestingly, despite such differences in TNF-α production, tumors inoculated into C3H/HeJ and C3H/HeN mice grew at a similar rate and contained an almost identical proportion of macrophages. Moreover, tumor cells purified from tumors grown in C3H/HeJ and C3H/HeN mice produced similar quantities of the TNF-α-inducible cytokine GM-CSF. Thus, although differences in the level of TNF-α produced within tumors grown in C3H/HeN and C3H/HeJ mice are readily demonstrable, such differences appear to have little direct impact on the outcome of tumor growth.