Abstract
Macrophages are important innate immune cells that are associated with two distinct phenotypes: a pro-inflammatory (or classically activated) subset with prototypic macrophage functions such as inflammatory cytokine production and bactericidal activity, and an anti-inflammatory (or alternatively activated (AAM)) subset linked with wound healing and tissue repair processes. In this study, we examined the effect of interlukein-6 on human and murine macrophage polarization. The results indicate that despite being commonly associated with pro-inflammatory functions and being implicated in the pathogenesis/pathophysiology of numerous inflammatory diseases, interleukin-6 can enhance the polarization of AAMs, based on increased expression of hallmark markers: arginase-1, Ym1 and CD206; this effect required the AAM differentiating cytokines, IL-4 and IL-13. Co-treatment of AAMs with IL-6 resulted in spontaneous release of IL-10, suppressed LPS-induced nitric oxide production and inhibited cytokine production by activated CD4+ T cells – immunoregulatory features not observed in the ‘parent’ IL-4+IL-13-induced AAM. The effect of IL-6 required signal transducer and activator of transcription (STAT)-3, was partially dependent on up-regulation of the IL4Rα chain, and was independent of autocrine IL-10. In the presence of IFNγ, IL-6 promoted the production of IL-1β and TNFα suggesting that this cytokine can enhance the phenotype to which a macrophage has committed. This finding may explain the pleiotrophic nature of IL-6, where it is associated with the perpetuation and enhancement of disease in inflammatory situations, but is also necessary for resolution of inflammation and adequate wound healing to occur in others. Thus, the potential benefit of IL-6 in promoting an AAM, with its’ anti-inflammatory and wound healing ability, may need to be considered in immunotherapies aimed at in vivo modulation or inhibition of IL-6.
Highlights
Macrophages are a major component of the innate immune system, and function as one of the earliest lines of defence against invading pathogens [1]
When applied as a co-treatment with IL-4+ IL-13, IL-6 significantly increased the expression of arginase 1 (Arg1), Ym1 and RELMa mRNA (Figure 1A)
We focused on the involvement of STAT3 in the up-regulation of Arg1 and Ym1, as other activators of this transcription factor (IL-10 (Figure 5) and IL-21) can enhance AAM polarization [9] and because there was a strong correlation between levels of phospho-STAT3 and Arg1/ Ym1 expression (Figure 6A). siRNA experiments revealed that knock-down of STAT3 (Figure 6B, inset) significantly inhibited the enhancement of arginase activity in AAM(IL-6) (Figure 6B) and inhibited the suppression of LPS-stimulated nitrite production (Figure 6C)
Summary
Macrophages are a major component of the innate immune system, and function as one of the earliest lines of defence against invading pathogens [1] They are critical in the maintenance of tissue homeostasis and the turnover of tissue and organ systems. It is known that different subpopulations of macrophages exist, carrying out distinct, but at times overlapping, functions [1] These subpopulations can be generally categorized as classically activated macrophages (CAMs or M1 macrophages), which are the prototypic pro-inflammatory macrophage subset induced by exposure to interferon-c (IFNc) and/or lipopolysaccharide (LPS), or alternatively activated macrophages (AAMs or M2 macrophages) [1,2]. Other markers, such as PPARc and CD206 can be used for identification of AAMs [5]
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