In murine models of experimental
endotoxemia, inflammatory
cytokines as well as antiinflammatory
interleukin-10 (IL-10) appear in the circulation after the injection of
lipopolysaccharide (LPS). There is considerable experimental evidence to suggest that the major function of endogenously produced
IL-10 is to down-regulate inflammatory
cytokine production. Indeed, the protective effects of exogenously administered
IL-10 against murine
endotoxin lethality have been shown to correlate with its ability to inhibit the LPS-induced production of
tumor necrosis factor-alpha (
TNF-alpha) and
interferon-gamma (IFN-gamma). While mouse
IL-10 (mIL-10) has been used in the majority of studies in murine
endotoxemia, we have found the human homolog to be equally effective in suppressing inflammatory
cytokine production and in protecting mice from
endotoxin lethality. However, we have recently observed that the LPS-induced endogenous
IL-10 response is enhanced when mice are treated with recombinant human
IL-10 (rhuIL-10). The upregulation of endogenous
IL-10 by exogenously administered rhuIL-10 is particularly evident in mice that are primed with Corynebacterium partum (Proprionibacterium acnes). In the present study, we have examined the potential contributions of the increased circulating levels of mouse
IL-10 to the inhibitory effects seen with rhuIL-10 on inflammatory
cytokine production and
endotoxin lethality. We show that pretreatment with a neutralizing anti-mouse
IL-10 monoclonal antibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-induced inflammatory
cytokine response in these mice. In contrast, the suppressive effects of the human
protein on inflammatory
cytokine responses are blocked completely by pretreating the animals with an anti-huIL-10 mAb. These data show that despite the up-regulated endogenous
IL-10 response, it is the exogenously administered rhuIL-10 that is directly responsible for the suppressed inflammatory
cytokine responses that are observed when the human
protein is given to endotoxemic mice.