Interleukin-6 upregulates the expression of PMP22 in cultured rat Schwann cells via a JAK2-dependent pathway

Abstract

The interleukin-6 (IL-6) family of cytokines is thought to be involved in the development and regeneration of peripheral nerves; however, their roles in myelination remain unclear. In this study, we examined the effects of IL-6 on the expression of genes for compact myelin proteins using Schwann cell cultures prepared by multiple explantation of adult rat sciatic nerves. In semi-quantitative reverse transcription-polymerase chain reaction analysis, stimulation of Schwann cells with IL-6 significantly increased the mRNA level of peripheral myelin protein 22 (PMP22), but not those of myelin protein zero and myelin basic protein. The increase in PMP22 mRNA was markedly suppressed by AG490, a Janus kinase 2 (JAK2) inhibitor, but not significantly by PD098059, a mitogen-activated protein kinase kinase inhibitor. Immunocytochemical staining revealed that IL-6 enhanced immunoreactivities for the phosphorylated forms of both JAK2 and signal transducer and activator of transcription 3 (STAT3), as well as that for PMP22. These results indicate that IL-6 can enhance PMP22 production in Schwann cells via a JAK2-dependent pathway by probably activating STAT3 and thus may contribute to myelination. E-mail address: shigeruy@med.kanazawa-u.ac.jp (S. Yokoyama). *Manuscript Click here to view linked References 2 ABSTRACTThe interleukin-6 (IL-6) family of cytokines is thought to be involved in the development

gp130 cytokines are positive signals triggering changes in gene expression and axon outgrowth in peripheral neurons following injury

“…Both Schwann cells and astrocytes are known to have receptors for these cytokines (Klein et al, 1997; Lee et al, 2009a, b; Wang et al, 2009; Ito et al, 2010; Kirsch et al, 2010), as do macrophages (Hendriks et al, 2008). An interesting example of a quite complicated set of intercellular processes involving LIF concerns this cytokine's ability to stimulate myelination (Ishibashi et al, 2006).…”

Low-Dose Pulsatile Interleukin-6 As a Treatment Option for Diabetic Peripheral Neuropathy

“…Exogenous administration of low-dose IL-6 to treat DPN  may be beneficial due to (1) increased insulin sensitivity in muscle (49), (2) decreased systemic inflammation (43, 44), (3) increased remyelination of axons (81–83), (4) increased nerve regeneration (96–98), (5) increased lipolysis (47, 48), and (6) decreased insulin secretion (34, 47). …”

“…Indeed, given studies in STZ-induced diabetic models have shown that delayed Wallerian degeneration is related to impaired axonal regeneration (79, 80), it may be inferred that in the diabetic state a lack of sufficient IL-6 signaling in Schwann cells may serve to delay Wallerian degeneration, thus further impairing nerve regeneration. In cultured rat Schwann cells, IL-6 upregulates genes for abundant low molecular weight glycoproteins in myelin such as myelin basic protein (MBP), peripheral myelin protein P 0 (81, 82) or peripheral myelin protein 22 (pmp22) via a JAK2-dependent pathway (83). Administration of IL-6/IL-6R fusion protein following nerve transection increased myelinated nerve fiber regrowth by fourfold (82).…”

Recovery of Genes Epigenetically Altered by the Histone Deacetylase Inhibitor Scriptaid and Demethylating Agent 5-Azacytidine in Human Leukemia Cells

“…PMP22, peripheral myelin protein 22, mediates Schwann cell growth and peripheral myelin compaction. Interleu-kin-6 upregulates the expression of PMP22 in cultured rat Schwann cells via a JAK2-dependent pathway (Ito et al, 2010). PMP22 is up-regulated in leukemia cells after combination treatment with 5-azacytidine and scriptaid.…”