Interleukin 10(EL,.10) Inhibits Cytokine Synthesis by Human Monocytes: An Autoregulatory Role of IL-10 Produced by Monocytes By Ren6 de Waal Malefyt,

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (I1-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. I1-10 was detectable 7 h after activation of the monocytes and maximal levels of I1-10 production were observed after 24--48 h. These kinetics indicated that the production of Ibl0 by human monocytes was relatively late as compared to the production of IDiot, I1-1/3, I1.-6, I1-8, tumor necrosis factor ot(TNFot), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of I1-10 by LPS activated monocytes was, similar to that of ILlot, FL-1/3, l'b6, I1-8, TNFc~ granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by II-4. Furthermore we demonstrate here that I1-10, added to monocytes, activated by interferon 3r LPS, or combinations of LPS and IFN-3' at the onset of the cultures, strongly inhibited the production of I1-1ot, I1-1B, I1-6, I1-8, TNFOt, GM-CSF, and G-CSF at the transcriptional level. Viral-I1-10, which has similar biological activities on human cells, also inhibited the production of TNFOt and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-I1-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced I1-10 inhibited the production of I1-1ot, I1-1B, I1-6, I1-8, TNFot, GM-CSF, and G-CSF. In addition, I1-10 had autoregulatory effects since it strongly inhibited I1-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced I1-10 was found to be responsible for the reduction in class II major histocompatibility complex (MHC) expression following activation of monocytes with LPS. Taken together our results indicate that I1-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to down.regulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.