Endogenous mouse interleukin-10 is up-regulated by exogenously administered recombinant human interleukin-10, but does not contribute to the efficacyof the human protein in mouse models of endotoxemia

In murine models of experimental endotoxemia, inflammatory cytokines as wel l as antiinflammatory interleukin-10 (IL-10) appear in the circulation afte r the injection of lipopolysaccharide (LPS). There is considerable experime ntal evidence to suggest that the major function of endogenously produced I L-10 is to down-regulate inflammatory cytokine production. Indeed, the prot ective effects of exogenously administered IL-10 against murine endotoxin l ethality have been shown to correlate with its ability to inhibit the LPS-i nduced production of tumor necrosis factor-alpha (TNF-alpha) and interferon -gamma (IFN-gamma). While mouse IL-10 (mIL-10) has been used in the majorit y of studies in murine endotoxemia, we have found the human homolog to be e qually effective in suppressing inflammatory cytokine production and in pro tecting mice from endotoxin lethality. However, we have recently observed t hat the LPS-induced endogenous IL-10 response is enhanced when mice are tre ated with recombinant human IL-10 (rhuIL-10). The upregulation of endogenou s IL-10 by exogenously administered rhuIL-10 is particularly evident in mic e that are primed with Corynebacterium parvum (Proprionibacterium acnes). I n the present study, we have examined the potential contributions of the in creased circulating levels of mouse IL-10 to the inhibitory effects seen wi th rhuIL-10 on inflammatory cytokine production and endotoxin lethality. We show that pretreatment with a neutralizing anti-mouse IL-10 monoclonal ant ibody (mAb) has no effect on the ability of rhuIL-10 to suppress an LPS-ind uced inflammatory cytokine response in these mice. In contrast, the suppres sive effects of the human protein on inflammatory cytokine responses are bl ocked 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 t he exogenously administered rhuIL-10 that is directly responsible for the s uppressed inflammatory cytokine responses that are observed when the human protein is given to endotoxemic mice. (C) 1999 Elsevier Science B.V. All ri ghts reserved.