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Interleukin 1-beta (IL1-beta) is a pleiotropic cytokine that stimulates a number of signal transduction pathways in cells, leading to different cellular responses. In this study we investigated the signal transduction pathways activated by IL1-beta in two different human cell lines: RD/TE671, a rhabdomyosarcoma, and EJ, a bladder-derived carcinoma. We showed that this cytokine induced the activation of protein kinase C-zeta (PKC-zeta) and the accumulation of a putative physiological PKC-zeta activator, phosphatidic acid [Limatola, Schaap, Moolenaar and van Blitterswijk (1994) Biochem. J. 304, 1001-1008]. Exogenously supplied phospholipase D, which generated cellular phosphatidic acid, was able to mimic the cytokine effect, supporting the hypothesis that this lipid second messenger might contribute to cytokine-induced PKC-zeta activation. In addition, we show that IL1-beta stimulation of BOSC23 cells, transiently overexpressing PKC-zeta, induced an increase in PKC-zeta autophosphorylation. These results give the first direct evidence that IL1-beta can activate this atypical PKC isoform and suggest that this enzyme might be involved in mediating some of the biological effects induced by IL1-beta.

Cytofluorimetric and reverse-transcription polymerase chain reaction (RT-PCR) analysis showed that adriamycinresistant (ADR R ), but not sensitive (WT), MCF-7 human mammary carcinoma cell lines express a4b1 and a5b1 integrins. ADR R cells adhere to fibronectin (FN), and only a5b1 is involved in cell adhesion to this glycoprotein, while a4b1 mediates cell binding to the cellular counter-receptor VCAM-1. Proliferation assays showed that FN, but not VCAM-1, delivers a mitogenic signal to quiescent ADR R MCF-7 cells. The activating signal is mediated by a5b1, since cell proliferation is inhibited in the presence of RGD peptide or specific antibody. Cell cycle analysis demonstrated that cell/FN interaction induces the re-entry of ADR R MCF-7 into S phase, and prevents them from undergoing serum deprivation-induced apoptosis. Our data suggest that the presence of a5b1 on the resistant cells enables them to draw advantage from FN for both cell growth and survival. Int.

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The in vitro inhibitory activity of Lonidamine on the aerobic glycolysis of normal as well as leukemic lymphocytes has been investigated. The extent of the impairment of lactate production induced by Lonidamine on normal thymus (T)- and bone marrow (B)-derived lymphocytes was found to be dependent on their source of origin, i.e. residing or circulating pool. Among leukemia tested ‘null’ and B cell leukemias appeared the most affected metabolically by the compound. Administration in vivo of the drug to the patient with B cell chronic leukemia resulted in a decrease of lactate production by leukemic cells comparable to that induced in vitro. These metabolic changes were paralleled in normal, as well as in leukemic cells by ultrastruc-tural lesions, mainly confined to the mitochondrial compartment.