IL-6-deficient mice resist myelin oligodendrocyte glycoprotein-induced autoimmune encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE) is induced by immunization with myelin components including myelin oligodendrocyte glycoprotein (MOG). Myelin-specific Th1 cells enter the central nervous system (CNS) via binding of very late antigen 4 (VLA-4) to the endothelial vascular cell adhesion molecule 1 (VCAM-1). In the present study, mice with a homologous disruption of the gene encoding IL-6 are found to be resistant to MOG-induced EAE as evidenced by absence of clinical symptoms, minimal infiltration of CD3+ T cells and monocytes into the CNS and lack of demyelination. The failure to induce EAE in IL-6-/- mice is not due to the absence of priming, since lymphocytes of immunized IL-6-/- mice proliferate in response to MOG and produce pro-inflammatory cytokines including IL-2 and IFN-gamma. However, in MOG-immunized IL-6-/- mice, serum anti-MOG antibody titers were found to be drastically reduced. This observation is unlikely to be responsible for resistance to EAE, because B cell-deficient (microMT) mice proved to be fully susceptible to the disease. A striking difference between MOG-immunized wild-type (wt) and IL-6-/- mice was the expression of endothelial VCAM-1 and ICAM-1, which were dramatically up-regulated in the CNS in wt but not in IL-6-/- mice. Taking into account recent studies on the role of VCAM-1 in the entry of Th1 cells into the CNS, the absence of VCAM-1 on endothelial cells in IL-6-/- mice may explain their resistance to EAE.

Cytokine production profiles in chronic relapsing–remitting experimental autoimmune encephalomyelitis: IFN-γ and TNF-α are important participants in the first attack but not in the relapse

“…Thus, IFN-γ and TNF-α may be associated with perivascular infiltration, but not with parenchymal infiltration, of inflammatory cells in the CNS in CREAE. IL-6 is a plurifunctional cytokine that is necessary for inducing cerebrovascular adhesion molecules, such as VCAM-1, which are essential for leukocyte trafficking to the CNS during EAE [21]. Other studies on EAE have demonstrated that the formation of CD4 + Th17 cells is driven by IL-6 together with TGF-β [22].…”

microRNA-301a regulation of a T-helper 17 immune response controls autoimmune demyelination

“…More recently another subset of T-helper cells, Th17, characterized by expression of the transcription factors retinoic acid receptor-related orphan receptor alpha (ROR-α) and retinoic acid receptor-related orphan receptor gamma t (ROR-γt) and by the production of IL-17, has been considered pivotal for the propagation of autoimmune demyelination (3). Mice with impaired numbers or function of Th17 cells, particularly mice deficient in the cytokines IL-6 or IL-23, are largely resistant to EAE (4)(5)(6). However, precise mechanisms governing the development and function of Th17 cells resulting in autoimmune demyelination are still unclear.…”

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

“…Its significance in one model system, experimental autoimmune encephalomyelitis (EAE), was supported by a number of studies. One of the most compelling being that IL-6 knockout mice were resistant to EAE (11,15) and had defects in the ability to activate antigen-specific T cells into effector status, despite having apparently normal T cell development (13). The IL-6 promoter contains both canonical KLF4 and CACCC binding sites, which led us to speculate that KLF4 might regulate the transcription of IL-6 and therefore have a downstream effect on production of IL-6.…”