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

Abstract

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.

Association tests with systemic lupus erythematosus (SLE) of IL10 markers indicate a direct involvement of a CA repeat in the 5′ regulatory region

“…1,2 It also inhibits certain functions of activated macrophages by down-regulating major histocompatibility complex (MHC) class II and B7 expression 3 and by inhibiting production of proinflammatory cytokines such as TNFa, IL1, IL6, IL8 and IL12. 1,4 Contrary to its T cell and macrophage inhibitory actions, IL10 has potent stimulatory effect on B lymphocytes, leading to their proliferation and differentiation. 5 SLE is a multisystem disease characterised by impaired T cell responses and dysregulation of B cell activation leading to B cell hyperactivity and production of autoantibodies.…”

Lipid-mediated gene transfer of viral IL-10 prolongs vascularized cardiac allograft survival by inhibiting donor-specific cellular and humoral immune responses

“…8,9 It should be noted that IL-10 also inhibits the production of monokines, including IL-1, IL-6, IL-8, TNF-␣, GM-CSF and G-CSF. 10,11 In addition to inhibiting cytokine production, IL-10 has also been shown to block accessory cell function of macrophages by down-regulating MHC class II expression and decreasing expression of the costimulatory molecule B7. [12][13][14][15] As a result of these activities, IL-10 is a potent suppressor of effector functions of macrophages and T cells.…”

“…19 Viral IL-10 shares many of the biologic activities of cellular IL-10, including inhibition of cytokine synthesis and accessory cell function. 5,10,12 However, vIL-10 does not posses the T cell costimulatory activities of cellular IL-10. [20][21][22] Thus, the introduction of vIL-10 into allografts by direct gene transfer should reduce immunogenicity, impair effective antigen presentation, and suppress macrophage and T cell effector function, thereby inhibiting graft rejection.…”

Interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α) are necessary in the early stages of induction of CD4 and CD8 cytotoxic T cells byMycobacterium lepraeheat shock protein (hsp) 65 kD

“…The suppressive function of IL-4 and IL-10 on T cell-mediated responses is well known [14], and the opposing effect of IFN-g [32] has been demonstrated employing M. leprae [33][34][35]. We observed an inhibition of cytolytic activity when normal PBMC were stimulated with hsp65 in the presence of high concentrations of type 2 cytokines (Fig.…”