We have examined in detail the activities of IL-13 on monokine production in vitro and compared its effects with those of IL-10 and IFN-gamma. IL-13 and IL-10 show qualitatively and quantitatively similar activities on cytokine production by monocytes when administered simultaneously with LPS i.e. inhibition of IL-1, IL-6 and TNF-alpha, up-regulation of IL1-ra. However when either LPS and IFN-gamma or fixed S. aureus Cowan (SAC) are used to activate monocytes, IL-10 is a much more potent inhibitor of TNF-alpha production than is IL-13. IL-10 is also an extremely potent inhibitor of IL-12 (p70) production when given with either SAC or LPS, while IL-13 has little effect. Indeed, IL-13 actually increases SAC-induced IL-12 production. When IL-13 is administered prior to the LPS stimulation, its modulation of cytokine production is drastically different. Production of IL-12, MCP-1, TNF-alpha and to a lesser extent IL-6 induced by LPS is now "primed", whereas that of IL-1, IL-8, and IL-10 is still inhibited. IL-10 does not show this "priming" effect, and is a dominant inhibitor of IL-13. The initial IL-13 priming effect is not however due to an inhibition of endogenous IL-10 production; nor is it due to inhibition of PGE2 production. The priming effect of IL-13 on IL-12 production is additive with that of IFN-gamma, and is partly independent of IFN-gamma. The earliest event in IL-13 priming so far noted is an increase in TNF-alpha mRNA production at 1-2 hours. IL-13 priming of IL-12 production can be completely abolished by anti-TNF-alpha antibodies suggesting that IL-13 may be priming via increased TNF-alpha expression, although merely substituting TNF-alpha for IL-13 does not reproduce the priming effect. IL-13 is a thus a more subtle immune regulator than IL-10 or IFN-gamma. When administered with LPS or SAC, it dampens the resulting inflammatory response, though in a more selective way than IL-10. In contrast, when it is added before an inflammatory signal, it primes an immunostimulatory monokine secretion profile resembling that of IFN-gamma, but without the proinflammatory IL-1 component. Early in response to an inflammatory stimulus, IL-13 may thus play an essentially anti-inflammatory role, switching to a primarily immunostimulatory role in the case of an ongoing infection.