Human MBP-specific T cells regulate IL-6 gene expression in astrocytes through cell-cell contacts and soluble factors.
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.
Colombatti
M
M
Section of Immunology, Department of Pathology, University of Verona, Italy.
Moretto
G
G
Tommasi
M
M
Fiorini
E
E
Poffe
O
O
Colombara
M
M
Tanel
R
R
Tridente
G
G
Ramarli
D
D
D001253:Astrocytes / Q000276:immunology* / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002448:Cell Adhesion / Q000276:immunology; D002450:Cell Communication / Q000276:immunology*; D002478:Cells, Cultured / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003001:Cloning, Molecular; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005333:Fetus; D005786:Gene Expression Regulation / Q000276:immunology*; D006801:Humans; D019012:Integrin beta1 / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics* / Q000378:metabolism; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D004676:Myelin Basic Protein / Q000276:immunology*; D016328:NF-kappa B / Q000378:metabolism; D010641:Phenotype; D010750:Phosphoproteins / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D050794:STAT1 Transcription Factor; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015534:Trans-Activators / Q000187:drug effects / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects / Q000276:immunology
D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D019012:Integrin beta1; D050856:Interferon Regulatory Factor-1; D015850:Interleukin-6; D004676:Myelin Basic Protein; D016328:NF-kappa B; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma