EFFECTS OF CALCITONIN GENE-RELATED PEPTIDE ON IRON METABOLISM, IL-6, AND MYELIN PROTEIN ZERO (MYELIN P0) EXPRESSION IN SCHWANN CELLS

Abstract

Calcitonin gene related peptide (CGRP), a neuropeptide up-regulated in the trigeminal ganglion (TG), has been associated with migraine pain and other orofacial pain symptoms. CGRP exerts its biological effects by binding to the CGRP receptors expressed on neurons and glial cells. Most of the recently published articles on pain modulation in the TG by glial cells have been focused on the satellite cells. This is due primarily to the intimate contact relationships between the satellite cells and the cell bodies of the primary sensory neurons in the TG. Schwann cells, on the other hand, are thought to play a passive role by producing myelin sheaths wrapping around axons. Emerging evidence suggests that Schwann cells may be participated in pain modulation. Thus, the present study aimed to elucidate the involvement of Schwann cells in responses to CGRP and dissect cellular mechanisms underlying such responses. Key molecular targets to be monitored in this study include P0 and IL-6. P0 was used as an activation marker of Schwann cells. Changes in IL-6 expression were monitored to determine whether Schwann cells could release IL-6 as part of their inflammatory response to CGRP. Since iron is an important cofactor required for a number of basic cellular functions, including ATP production and myelin formation and involved in the activation of NF-κB, which plays an essential role in the regulation of genes involved in inflammatory responses in Schwann cells. Therefore, this study also aimed to determine the relationship between iron metabolism and response of Schwann cells to CGRP. The TfR were used to monitor intracellular iron levels following the stimulation of CGRP. Results show (1) CGRP stimulates P0 expression in Schwann cells and further suggest that P0 can be used as a specific marker for CGRP-induced Schwann cell activation, (2) CGRP-upregulated P0 expression in Schwann cells is mediated by the transcription factor Krox-20, (3) CGRP induces IL-6 production and IL-6R expression in Schwann cells and suggest that IL-6 released from Schwann cells should have both a paracrine and an autocrine effects, (4) CGRP-stimulated Schwann cell activation is mediated by NF-κB and (5) CGRP stimulates changes in iron metabolism in Schwann cells and Schwann cells possess a regulatory mechanism to maintain cellular iron homeostasis. In summary, the present study provides new evidence involving Schwann cell biology and the essential role of iron and IL-6 in neurogenic pain.