Human MBP‐specific T cells regulate IL‐6 gene expression in astrocytes through cell–cell contacts and soluble factors

Abstract

One of the distinctive features of multiple sclerosis (MS) attacks is homing to the CNS of activated T cells able to orchestrate humoral and cell-based events, resulting in immune-mediated injury to myelin and oligodendrocytes. Of the complex interplay occurring between T cells and CNS constituents, we have examined some aspects of T-cell interactions with astrocytes, the major components of the glial cells. Specifically, we focused on the ability of T cells to regulate the gene expression of interleukin-6 (IL-6) in astrocytes, based on previous evidence showing the involvement of this cytokine in CNS disorders. We found that T-cell adhesion and T-cell soluble factors induce IL-6 gene expression in U251 astrocytes through distinct signaling pathways, respectively, resulting in the activation of NF-kappaB and IRF-1 transcription factors. In a search for effector molecules at the astrocyte surface, we found that alpha3beta1 integrins play a role in NF-kappaB activation induced by T-cell contact, whereas interferon-gamma (IFN-gamma) receptors dominate in IRF-1 induction brought about by T-cell-derived soluble factors. Similar phenomena were observed also in normal fetal astrocyte cultures. We therefore propose that through astrocyte induction, T cells may indirectly regulate the availability of a cytokine which is crucial in modulating fate and behavior of cell populations involved in the pathogenesis of MS inflammatory lesions.

Spinal activity of interleukin 6 mediates myelin basic protein-induced allodynia

“…Accordingly, we suggest that T cell recruitment and Th17 polarization after IS MBP84-104 [10] relate to the concomitant increase in IL-6 expression, which we find to be T cell-independent. Th17-released IL-17 enhances the glial IL-6 production resulting in a positive feedback loop [63], thereby augmenting further the IL-17 synthesis in Th17 cells [64, 65]. While systemic T cell activation, causing demyelination, is a likely cause of pain associated with EAE [51], direct IS administration of a pure MBP84-104 peptide into an intact nerve confirms that the activity of the MBP epitopes is sufficient to induce robust and lasting pain.…”

Inhibition of a novel specific neuroglial integrin signaling pathway increases STAT3-mediated CNTF expression

“…T-cell adhesion induces IL-6 in cultured astrocytes through activation of α3β1 integrin [65]. Stretch-induced IL-6 expression in endothelial cells is mediated by α5β1 integrin [66].…”

“…In contrast, FAK-driven JNK and ERK both regulate FGF2-induced astroglial migration [70]. The NF-kappaB pathway mediates α3β1 and α5β1 integrin stimulation of IL-6 in astrocytes [65] and endothelial cells [66]. These integrins do not regulate CNTF.…”

A Transcription Factor Map as Revealed by a Genome-Wide Gene Expression Analysis of Whole-Blood mRNA Transcriptome in Multiple Sclerosis

“…For example, it has previously been observed that members of the NF-kappaB, STAT, AP-1 and E2F families [30]–[56], IRF-1 [36], [46], [47], [57], IRF-2 [58], IRF-5 [59], IRF-8 [20], CREB [36], [46], PPARgamma and PPARalpha [60]–[68], SP1 [59], SP3 [69]–[71], RORC [72], NR4A2, TCF2 [73], ETS-1 [74] and FOXP3 [75]–[85] may be implicated in MS and its disease subtypes. This paper aims to complement the companion study by uncovering, thanks to combinatorial optimization and differential co-expression methods and a different focus in the analysis, transcription factors that potentially dysregulate many genes in MS.…”