Abstract
Recombinant mouse interleukin 10 (IL-10) was exceedingly potent at suppressing the ability of mouse peritoneal macrophages (m phi) to release tumor necrosis factor alpha (TNF-alpha). The IC50 of IL-10 for the suppression of TNF-alpha release induced by 0.5 microgram/ml lipopolysaccharide was 0.04 +/- 0.03 U/ml, with as little as 1 U/ml suppressing TNF-alpha production by a factor of 21.4 +/- 2.5. At 10 U/ml, IL-10 markedly suppressed m phi release of reactive oxygen intermediates (ROI) (IC50 3.7 +/- 1.8 U/ml), but only weakly inhibited m phi release of reactive nitrogen intermediates (RNI). Since TNF-alpha is a T cell growth and differentiation factor, whereas ROI and RNI are known to inhibit lymphocyte function, it is possible that m phi exposed to low concentrations of IL-10 suppress lymphocytes. m phi deactivated by higher concentrations of IL-10 might be permissive for the growth of microbial pathogens and tumor cells, as TNF-alpha, ROI, and RNI are major antimicrobial and tumoricidal products of m phi. IL-10's effects on m phi overlap with but are distinct from the effects of the two previously described cytokines that suppress the function of mouse m phi, transforming growth factor beta and macrophage deactivation factor. Based on results with neutralizing antibodies, all three m phi suppressor factors appear to act independently.
Highlights
Supernatants from COS7 cells transfected with mlL-10 eDNA (1,000 U/ml, where 1 U caused half-maximal response of the MC/9 mast cell line as described [20]; LPS content at 100 U/ml < 10 pg/ml) and control supernatants from mock transfected cells (LPS content at a 1:10 dilution < 10 pg/ml) were kindly provided by Dr K
Moore (DNAX, Palo Alto, CA; 1 MC/9 U/ml is equal to 1 cytokine synthesis inhibitory factor (CSIF) U/ml, personal communication)
A unit of mObdeactivating factor (MDF) is defined as that amount of MDF in a final culture volume of 0.125 ml that causes 50% suppression of PMA-triggered mO HzO2-releasingcapacity after a 48-h incubation [10]. rmlFN~ and rmTNF-c~ were kindly provided by Genentech (South San Francisco, CA). rhTGF~I was a gift of Amgen, Inc. (Thousand Oaks, CA)
Summary
FemaleCD1 mice (8-12 wk old) were from the Charles River Breeding Laboratories (Wilmington, MA). Supernatants from COS7 cells transfected with mlL-10 eDNA (1,000 U/ml, where 1 U caused half-maximal response of the MC/9 mast cell line as described [20]; LPS content at 100 U/ml < 10 pg/ml) and control supernatants from mock transfected cells (LPS content at a 1:10 dilution < 10 pg/ml) were kindly provided by Dr K. Ascitesfluid containing a neutralizing rat IgM mAb against mlL-10 (SXC1 [21]; LPS content
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