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.
Subject(s)
Astrocytes/immunology , Cell Communication/immunology , Gene Expression Regulation/immunology , Interleukin-6/genetics , Multiple Sclerosis/immunology , Myelin Basic Protein/immunology , T-Lymphocytes/immunology , Astrocytes/metabolism , Binding Sites/drug effects , Binding Sites/physiology , Cell Adhesion/immunology , Cells, Cultured/drug effects , Cells, Cultured/immunology , Cells, Cultured/metabolism , Cloning, Molecular , DNA-Binding Proteins/drug effects , DNA-Binding Proteins/immunology , DNA-Binding Proteins/metabolism , Fetus , Humans , Integrin beta1/drug effects , Integrin beta1/immunology , Integrin beta1/metabolism , Interferon Regulatory Factor-1 , Interferon-gamma/pharmacology , Interleukin-6/metabolism , Multiple Sclerosis/genetics , Multiple Sclerosis/physiopathology , NF-kappa B/metabolism , Phenotype , Phosphoproteins/drug effects , Phosphoproteins/immunology , Phosphoproteins/metabolism , Phosphorylation/drug effects , STAT1 Transcription Factor , T-Lymphocytes/metabolism , Trans-Activators/drug effects , Trans-Activators/metabolism , Transcription, Genetic/drug effects , Transcription, Genetic/immunology , Up-Regulation/drug effects , Up-Regulation/immunologySubject(s)
Bronchial Diseases/drug therapy , Mezlocillin/therapeutic use , Acute Disease , Adult , Aged , Chronic Disease , Clinical Trials as Topic , Female , Humans , Male , Middle AgedABSTRACT
Twenty-seven consecutive patients with locally advanced or metastatic non-small cell lung carcinoma were treated with low-dose cisplatin and etoposide. Out of 25 evaluable patients, 8% had a partial response, 56% had stable disease and 36% had disease progression. The overall median survival was 4 months. The survival of the two responding patients was 5 and 6.5 months. The patients showing stable disease or progression had a median survival of 6 and 3 months, respectively. Toxicity including myelosuppression, nephrotoxicity and gastrointestinal side effects was generally mild. In this trial the combination of low-dose cisplatin and etoposide did not yield the same positive results observed by other authors. The different selection of patients and criteria of response evaluation could represent the main reason for this disagreement in results.
