Inhibition of tumour necrosis factor and natural cytotoxic cell lytic activities by a spleen cell-elaborated factor.

Natural cytotoxic (NC) cell lytic activity is mediated by tumour necrosis factor (TNF), a protein with potent cytolytic activity on certain target cells. TNF also appears to mediate a wide range of other important biological activities (e.g. interferon-like anti-viral activity, induction of granulocyte-monocyte colony-stimulating factor, mediation of endotoxin-induced shock). Evidence is presented here that spleen cells from normal, untreated mice produce a factor(s) that inhibits both NC and TNF cytolytic activity. The factor(s) has a molecular weight greater than 10,000. Since indomethacin inhibits production by spleen cells of the NC/TNF inhibitory factor, it is suggested that prostaglandins are involved in the regulation of its production. Additionally, these studies indicate that the factor(s) does not function by inactivation of either NC effectors or TNF molecules, or by inhibition of the binding of NC cells or TNF to targets. Instead, the data suggest that the factor(s) acts on the targets rendering them refractory to TNF binding. Moreover, since the factor(s) acts slowly and requires protein synthesis in the target to function, it appears that the inhibitory activity is mediated via de novo-synthesized proteins from the target cells. At present, it is not known whether such a factor functions in vivo, although it is conceivable that its in vivo role is to modulate the pathological potential of TNF by protecting certain cells from NC or TNF lysis.