IL-6 Regulates In Vivo Dendritic Cell Differentiation through STAT3 Activation

Abstract

Dendritic cells (DCs) orchestrate immune responses according to their state of maturation. In response to infection, DCs differentiate into mature cells that initiate immune responses, while in the absence of infection, most of them remain in an immature form that induces tolerance to self Ags. Understanding what controls these opposing effects is an important goal for vaccine development and prevention of unwanted immune responses. A crucial question is what cytokine(s) regulates DC maturation in the absence of infection. In this study, we show that IL-6 plays a major role in maintaining immature DCs. IL-6 knockout (KO) mice had increased numbers of mature DCs, indicating that IL-6 blocks DC maturation in vivo. We examined this effect further in knockin mice expressing mutant versions of the IL-6 signal transducer gp130, with defective signaling through either Src homology region 2 domain-containing phosphatase 2/Gab/MAPK (gp130F759/F759) or STAT3 (gp130FxxQ/FxxQ), and combined gp130 and IL-6 defects (gp130F759/F759/IL-6 KO mice). Importantly, we found STAT3 activation by IL-6 was required for the suppression of LPS-induced DC maturation. In addition, STAT3 phosphorylation in DCs was regulated by IL-6 in vivo, and STAT3 was necessary for the IL-6 suppression of bone marrow-derived DC activation/maturation. DC-mediated T cell activation was enhanced in IL-6 KO mice and suppressed in gp130F759/F759 mice. IL-6 is thus a potent regulator of DC differentiation in vivo, and IL-6-gp130-STAT3 signaling in DCs may represent a critical target for controlling T cell-mediated immune responses in vivo.

IL-1β Induces IL-6 Expression in Human Orbital Fibroblasts: Identification of an Anatomic-Site Specific Phenotypic Attribute Relevant to Thyroid-Associated Ophthalmopathy

“…The cytokine may also exert direct actions that promote T cell migration; these effects are mediated through MAPK, PI3K, and the Jak/STAT pathways (46). It also influences dendritic cell and macrophage differentiation in vitro (47,48) and in vivo (49). It is noteworthy that STAT3 activation is required for the suppression by IL-6 of LPS-dependent cell maturation.…”

KLF4 Modulates Expression of IL-6 in Dendritic Cells via Both Promoter Activation and Epigenetic Modification

“…Among these are C/EBP (22), NF-B (23), and Stat3 (24). Similarly, a number of different stimuli to monocytes and dendritic cells will elicit the production of this cytokine.…”

Mage-b vaccine delivered by recombinant Listeria monocytogenes is highly effective against breast cancer metastases

“…Interleukin-6 is a potent regulator of DC differentiation (Park et al, 2004), and is able to initiate the expression of STAT3 in DC. High levels of STAT3 can prevent the maturation of DC and subsequent Anti-IL-6 (50 g ml -1 ) IL-6 (100 pg ml -1 ) Figure 6 Effect of IL-6 on Mage-b-induced immune responses in vitro.…”