Emerging role of IL-16 in cytokine-mediated regulation of multiple sclerosis

- We summarize the regulatory roles of IL-16 in relapsing EAE and MS.
- IL-16 exclusive binds and signals through CD4 receptor.
- IL-16 regulates migration of all CD4+ T cells regardless of their activation state.
- IL-16 facilitates the expansion of CD4+CD25+ Treg cells.
- IL-16-mediated mechanisms will help in developing CD4+ T cell-targeted therapies.

Cytokines are pleiotropic soluble mediators of cellular functions. Cytokines are critical in immune pathogenesis of human diseases, including autoimmune CD4+ T cell mediated chronic inflammatory, demyelinating and neurodegenerative diseases of the central nervous system (CNS), multiple sclerosis (MS). In MS and its experimental model, experimental autoimmune encephalomyelitis (EAE), chronic persistence and/or reoccurrence of inflammation in the CNS causes chronic progressive or relapsing disease, accompanied with demyelination and damage to axons and oligodendrocytes, which ultimately leads to paralysis and disability. As opposed to other cytokines, whose effects are not limited to the CD4+ T cell subset, IL-16 exerts its biological properties by exclusive binding and signaling through CD4 receptor. IL-16 selectively regulates migration of all CD4 expressing T cells regardless of their activation state, which is of critical importance for immune modulation and potential therapy of MS. Other major biological properties of IL-16 essential for the function of CD4+ T cells include regulation of: T cell activation, CD25 expression, MHC class II expression, dendritic cell (DC)-T cell cooperation, B cell-T cell and T cell-T cell cooperation, inflammatory cytokine production and modulation of chemokine regulated T cell chemo-attraction. In this article we outline immune pathogenesis of the disease necessary to understand significance of cytokines and IL-16 in MS regulation. We revisit cytokine regulation with emphasis on involvement of IL-16 mechanisms, implicated in MS progression and important for development of new therapies. We emphasize the significance of similar IL-16 mechanisms for other chronic inflammatory CNS diseases.