Table 2.
Important effects of interleukin-6 (IL-6) on immunocompetent cells involved graft-versus-host disease (GVHD) and on GVHD target organs.
| IL-6 effects on immunocompetent cells |
|---|
| T cells: Membrane-bound IL-6R mainly expressed on naïve and memory T cells (60, 72). |
| Naïve T cells: IL-6 causes STAT3 activation, resulting in SOCS1 expression and thereby inhibited Th1 polarization (73). |
| Th1 cells: Suppressed Th1 development (73). |
| Th2 cells: Enhanced Th2/polarization/development through STAT3 dependent c-maf expression and STAT3 independent NFAT expression (73). |
| Th17 cells: Enhanced Th17 development through IL-6- and IL-21-induced STAT3 activation followed by increased RORγT expression (56, 73–76). Differentiation from naïve T cells to Th17 relies largely on classical IL-6 signaling, whereas maintenance of Th17 cells depends on trans-signaling (60). STAT3 activation in naïve T cells by mIL-6R/IL-6 complex on the dendritic cells (cluster signaling) has been shown to be important for the development of pathogenic Th17 cells (53). |
| Th22 cells: The development depends on combined effects of IL-6, TNFα, IL-1β, and the aryl hydrocarbon receptor (77). |
| Tregs: Suppressed Treg development, inhibition of FOXP3 expression. Indirect effects of IL-6 may increase Treg development through increased release of anti-inflammatory cytokines (78). |
| Tfh: IL-6 seems to commit T cells to Thf differentiation (79, 80). |
| Dendritic cells and monocytes |
| Dendritic cells: Inhibits differentiation of dendritic cell from bone marrow progenitors, and decreased responsiveness of dendritic cells. STAT3 activation seems important for these effects (81, 82). |
| Monocytes: Increased M-CSF expression favors differentiation into macrophages rather than dendritic cells (83). |
| B cells: A key factor for regulation of B cell survival and maturation through both direct as well as indirect effects by stimulation of Tfh development (79, 80). Supports development into long-lived plasma cells (84). |
| Mesenchymal stem cells (MSCs): MSCs have unique immunomodulatory effects and have therefore been used in the treatment of acute and chronic GVHD. MSCs suppress Th1 and Th17 cells and induce Treg expansion through the release of multiple cytokines, including IL-6 and the IL-6 family cytokine LIF (85). Pro-inflammatory signals upregulate the constitutive IL-6 release by MSCs (86), and autocrine IL-6 stimulation will thereafter induce the release of immunosuppressive prostaglandin E2 by the MSCs (87). Furthermore, LIF secretion by MSCs inhibits T-cell proliferation in mixed lymphocyte reaction and seems to enhance the generation of Tregs (88). Autocrine IL-6 stimulation seems important for their survival, maintenance of stemness, and regulation of proliferation; ERK1/2 seems important for these effects (89, 90). MSC/T cell cross talk seems to increase local IL-6 levels (91). |
| Effects of IL-6 on leukocyte migration during local inflammation |
|