Interleukin 10(IL-10) inhibits cytokine synthesis by human monocytes an autoregulatory role of IL-10 produced by monocytes

• Published in: The Journal of experimental medicine 1991-11, Vol.174 (5), p.1209-1220
• Main Authors: DE WAAL MALEFYT, R, ABRAMS, J, BENNETT, B, FIGDOR, C. G, DE VRIES, J. E
• Format: Article
• Language: English
• Subjects: Analysis of the immune response. Humoral and cellular immunity; Base Sequence; Biological and medical sciences; Cells, Cultured; Cytokines - biosynthesis; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Granulocyte-Macrophage Colony-Stimulating Factor - biosynthesis; Histocompatibility Antigens Class II - analysis; Homeostasis; Humans; Immunobiology; Interferon-gamma - biosynthesis; Interferon-gamma - pharmacology; Interleukin-1 - biosynthesis; Interleukin-10 - genetics; Interleukin-10 - physiology; Interleukin-4 - pharmacology; Interleukin-6 - biosynthesis; Lipopolysaccharides; Lymphokines, interleukins ( function, expression); Molecular Sequence Data; Monocytes - metabolism; Regulatory factors and their cellular receptors; RNA, Messenger - analysis; Transcription, Genetic; Transforming Growth Factor beta - genetics
• ISSN: 0022-1007; 1540-9538
• DOI: 10.1084/jem.174.5.1209

In the present study we demonstrate that human monocytes activated by lipopolysaccharides (LPS) were able to produce high levels of interleukin 10 (IL-10), previously designated cytokine synthesis inhibitory factor (CSIF), in a dose dependent fashion. IL-10 was detectable 7 h after activation of the monocytes and maximal levels of IL-10 production were observed after 24-48 h. These kinetics indicated that the production of IL-10 by human monocytes was relatively late as compared to the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, tumor necrosis factor alpha (TNF alpha), and granulocyte colony-stimulating factor (G-CSF), which were all secreted at high levels 4-8 h after activation. The production of IL-10 by LPS activated monocytes was, similar to that of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, granulocyte-macrophage colony-stimulating factor (GM-CSF), and G-CSF, inhibited by IL-4. Furthermore we demonstrate here that IL-10, added to monocytes, activated by interferon gamma (IFN-gamma), LPS, or combinations of LPS and IFN-gamma at the onset of the cultures, strongly inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF at the transcriptional level. Viral-IL-10, which has similar biological activities on human cells, also inhibited the production of TNF alpha and GM-CSF by monocytes following LPS activation. Activation of monocytes by LPS in the presence of neutralizing anti-IL-10 monoclonal antibodies resulted in the production of higher amounts of cytokines relative to LPS treatment alone, indicating that endogenously produced IL-10 inhibited the production of IL-1 alpha, IL-1 beta, IL-6, IL-8, TNF alpha, GM-CSF, and G-CSF. In addition, IL-10 had autoregulatory effects since it strongly inhibited IL-10 mRNA synthesis in LPS activated monocytes. Furthermore, endogenously produced IL-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 IL-10 has important regulatory effects on immunological and inflammatory responses because of its capacity to downregulate class II MHC expression and to inhibit the production of proinflammatory cytokines by monocytes.