Delivery of hyper-interleukin-6 to the injured spinal cord increases neutrophil and macrophage infiltration and inhibits axonal growth

Abstract

Cytokine growth factors of the interleukin (IL)-6 family have recently been shown to play an important role in central nervous system (CNS) development, repair, and inflammation. These cytokines, which interact via specific membrane receptors, share a signal-transducing receptor subunit, glycoprotein 130 (gp130). Gp130 is expressed by motoneurons in the gray matter of the rat spinal cord and by several brainstem nuclei that project to the spinal cord including the red, reticular, and vestibular nuclei. In this study, we examined whether stimulation of gp130 signaling, with the use of grafts of fibroblasts genetically modified to deliver the fusion protein, hyper-IL-6 (H-IL-6), which consists of the cytokine growth factor, IL-6, and its alpha receptor, would elicit growth of injured spinal cord axons. Particular emphasis was placed on examining the potentially competing effects of growth factor versus proinflammatory influences of H-IL-6 in the context of spinal cord injury. Our results demonstrated that grafts delivering H-IL-6 induce a sixfold increase in the number of neutrophils (P < 0.05) and a twofold increase in the areas of spinal tissue occupied by macrophages and activated microglia (P < 0.01) at the site of the spinal cord injury when compared with control grafts. Of note, this augmentation in inflammatory cell infiltration correlated with a significant twofold increase in lesion size (P < 0.05) and a fourfold reduction in axonal growth (P < 0.01) at the lesion site. Thus, potential neurotrophic properties of this cytokine family of growth factors must be balanced against their inflammatory properties when considering therapeutic application to CNS injury.