In parallel to that, IL-10 is selleck chemicals llc capable of inducing anergy of T lymphocytes by directly inhibiting the phosphorylation of CD28. In that way, one of the basic immunosuppressive mechanisms is executed by IL-10 by inducing a tolerogenic type of dendritic cells with reduced HLA-II and B7 expression and by suppression of CD28 (the partner of B7) expression on the surface of the T lymphocytes. This “two sided” suppression of the second signal which is unconditionally needed for activation of the T lymphocytes induces a deep anergy in this cell population[37,69-71,76]. Further on, IL-10 is directly engaged in the induction

of immune tolerance by two types of T regulatory lymphocytes: Tregs and Tr1[76]. IL-10 is one of the cytokines related to the generation of Tregs[73] which secretes

IL-10 by itself and this process has been described both for “natural” FoxP3+ Tregs and for FoxP3+ Tregs generated after response to a specific antigen[70,73,80]. A specific feature of IL-10 and some other cytokines is that the producing cells are both the source and target of the cytokine effect and this predominantly affects the dendritic and T regulatory cells. A good example is that tolerogenic DCs secrete IL-10 and thus induce the generation of regulatory T helpers (FoxP3 and Tr1) which secrete IL-10 inducing tolerogenic phenotype of DCs[70,71,76]. Likewise, many other cytokines IL-10 can also act in an autocrine loop. The effect of IL-10 is mediated via its binding to its specific receptor (IL-10R) and subsequent interaction between JAK1 and STAT-3[73,77], a mechanism which is common for many other cytokines. Besides the antigen-presenting cells and particularly tolerogenic DCs, Tregs and Tr1, other immune cells secrete IL-10 and these include T and B lymphocytes, NK cells, neutrophils

and macrophages[76,80]. The role of IL-10 secreted by Th2 helpers is well known[76,80] but some recently published data show that this cytokine in a somewhat paradoxical manner is secreted by both Th1 and Th17 cells. Quite often these “double secreting” cells (IL-10 simultaneously with Batimastat IFNγ or IL-17) use IL-10 to suppress their own pro-inflammatory effect, both directly and/or with the help of tolerogenic antigen-presenting cells[71,74]. IL-10 is considered to be a classical cytokine inducing immune tolerance but there are data which show that, similarly to most cytokines, IL-10 acts in more than one way. Its pro-immune effect has been described in tumorigenesis[70,72] and IL-10 is detected in a tumor environment and shown to have an anti-tumor effect. It is assumed that this effect is due to inhibition of the tumor angiogenesis and enhancement of the nitric oxide secretion. IL-10 is also connected to the inhibition of the expression of MHC by the tumor cells which makes them an easier target for the NK cells.