F Herrmann

Interleukin-6 in clinical medicine.

SummaryThis article covers the basic biological functions of interleukin-6 (IL-6) in man. Three major topics are addressed more closely: the involvement of IL-6 in various disease states, particularly those of hematopoietic origin; the diagnostic usefulness of IL-6 measurements in biological fluids; the possible use of IL-6, IL-6 antagonists or IL-6 derivatives as therapeutic means.

Phase I trial of recombinant human tumour necrosis factor α in patients with advanced malignancy

Abstract A phase I clinical trial was conducted with recombinant human tumour necrosis factor alpha (rhTNF-α) in 62 patients with advanced malignancy refractory to previous standard therapy. rhTNF-α was given as a 30 min infusion twice a day at 6 h intervals. A total of 10 different dose levels was escalated in cohorts of 6 patients ranging from 2.5 to 200 μg/m 2 twice a day for 5 days every second week for a total of 8 weeks followed by a 4-week observation period. Major side-effects of TNF-α therapy, seen in almost all patients studied, were fever and chills. As dose-limiting side-effects hypotension and liver toxicity were recorded in 4 of 5 patients treated with 200 μg/m 2 twice a day. Pharmacokinetic studies revealed a TNF-α serum half-life of 13 to 25 min, a dose-dependent decrease in TNF clearance, and a dose-dependent increase in the area under the time/concentration curve. No anti-TNF-α antibodies could be detected, except in 1 patient. Tumour response to TNF treatment was poor. Only in 3 of 57 evaluable patients was partial tumour regression observed.

Interleukin 6: presence and future

SummaryThis review article deals with the basic biological characteristics of the multifunctional cytokine interleukin-6 (IL-6) in man. Three central issues will be addressed more closely: the pathophysiological role of unbalanced IL-6 production in various disease states, the diagnostic usefulness of measurements of IL-6 in biological fluids, and the possible role of IL-6, IL-6 antagonists, and IL-6 derivatives as therapeutic tools in clinical medicine.

Regulation of M-CSF Expression by M-CSF: Role of Protein Kinase C and Transcription Factor NFkB

Macrophage-colony-stimulating factor (M-CSF), also referred to as CSF-1, regulates the survival, growth, differentiation and functional activity of monocytes by binding to a single class of high-affin

Mechanisms of differential regulation of interleukin-6 mRNA accumulation by tumor necrosis factor alpha and lymphotoxin during monocytic differentiation

In the present report we compare the capacity of two related cytokines, tumor necrosis factor (TNF) alpha and lymphotoxin (LT), to modulate mRNA levels of interleukin‐6 (IL‐6) in cells representing different stages of monocytic differentiation including the human leukemia cell lines HL 60, U 937, THP‐1, MonoMac 1 and peripheral blood monocytes. We show that the capacity of TNF alpha and LT to induce IL‐6 mRNA accumulation increases as monocytic differentiation proceeds with TNF alpha being more potent than LT, suggesting that alternate pathways may be used by differentiating cells to control expression of IL‐6. In contrast, in monocytes which constitutively synthesize IL‐6 transcripts, TNF alpha and LT treatment had opposite effects on levels of IL‐6 mRNA accumulation. In these cells TNF alpha enhanced steady state levels of IL‐6 transcripts due to mRNA stabilization, whereas LT shortened IL‐6 mRNA half‐life, most likely due to induction of a RNA destabilizer since LT‐mediated downregulation of levels of IL‐6 mRNA in monocytes could be prevented by inhibition of protein synthesis. Neither TNF alpha nor LT altered IL‐6 mRNA accumulation by interfering with preexisting transcription factors since both TNF alpha and LT required de novo protein synthesis to exert their effects.

Regulation of gene expression of macrophage-colony stimulating factor in human fibroblasts by the acute phase response mediators interleukin (IL)-1β, tumor necrosis factor-α and IL-6

Fibroblasts constitute a major element of the bone marrow stroma. They play a pivotal role in blood cell development by providing the scaffolding required for cellular organization and tissue cohesion and by producing soluble molecules including colony stimulating factors (CSFs) and various interleukins regulating hematopoiesis. Our data demonstrate that the acute phase response mediators interleukin (IL)‐1 β, tumor necrosis factor (TNF)‐α and IL‐6 which are abundantly produced by activated monocytes, enhance levels of macrophage‐colony stimulating factor (M‐CSF) in fibroblasts by both transcriptional and post‐transcriptional mechanisms. The action of these proteins to induce M‐CSF transcript levels was dependent on synthesis of new proteins and was not mediated by protein kinase C (PKC) stimulation as depletion of cellular PKC pools by prolonged exposure of fibroblasts to phorbolester TPA did not prevent factor induced synthesis of M‐CSF transcripts. However, blockade of PKC by the isoquinoline sulfonamide derivative H7 and thus inhibition of phosphorylation was associated with augmentation of the fibroblasts response to TNF‐α and IL‐6.

Interleukin-4 regulates mRNA accumulation of macrophage-colony stimulating factor by fibroblasts: synergism with interleukin-1β

Summary. We demonstrate that macrophage‐colony stimulating factor (M‐CSF) is expressed in human fibroblasts at the mRNA and protein level. Following activation with both interleukin (IL)‐1β and IL‐4. fibroblasts synthesized M‐CSF transcripts detectable by Northern blot analysis with peak expression occurring at 8 h and 12 h, respectively. Exposure of fibroblasts to both cytokines resulted in M‐CSF protein release at 60 h of c. 500 U/ml (for IL‐1β) and 1000 U/ml (for IL‐4), relative to a control preparation of recombinant human M‐CSF in a murine bone marrow colony assay. Both interleukins synergized to enhance M‐CSF mRNA accumulation and their ability to induce M‐CSF transcripts could be abolished by treatment with specific neutralizing antibodies. These observations provide support for the idea that fibroblasts may control monocyte/macrophage development and function, and that IL‐1β and IL‐4 are involved in the regulation of this process.

THE ROLE OF COLONY-STIMULATING FACTORS IN ACUTE-LEUKEMIA

SummaryThis article summarises the effects of colony-stimulating factors and related molecules on leukemia blasts by focussing on autocrine and paracrine growth control. This information may lead to a better understanding of the pathobiology of this highly malignant disorder, and may have therapeutic implications.

Differential regulation of interleukin-6 expression in human fibroblasts by tumor necrosis factor-α and lymphotoxin

The treatment of human diploid fibroblasts with tumor necrosis factor (TNP)‐α and with lymphotoxin (LT) is associated with induction of interleuk‐in‐6 (IL‐6) transcripts with TNF‐α being 10‐fold more potent than LT. Here we report on the TNF‐α/LT‐induced signaling mechanisms responsible for the regulation of IL‐6 gene expression in these cells. Run‐on assays demonstrated that both TNF‐α and LT increase IL‐6 mRNA levels by transcriptional activation of this gene. Stability studies of IL‐6 transcripts in fibroblasts showed that TNF‐α delayed IL‐6 mRNA decay but not LT. The induction of IL‐6 transcripts by TNF‐α and LT was not inhibited by the isoquinoline sulfonamide derivative H7. Similarly, depletion of protein kinase C (PKC) by 12‐O‐tetradecanoyl‐phorbol 13‐acetate (TPA) did not change the ability of TNF‐α and LT to induce IL‐6 transcripts, demonstrating that stimulation by these agents may not be mediated by activation of PKC. Stimulation of IL‐6 transcripts in fibroblasts did also not require new protein synthesis as exposure to the protein synthesis inhibitor cycloheximide (CHX) enhanced accumulation of IL‐6 mRNA in the presence or absence of TNF‐α or LT.

Induction of monocytic differentiation and modulation of the expression of c-fos, c-fms and c-myc protooncogenes in human monoblasts by cytokines and phorbolester.

SummaryGrowing evidence suggests that proto-oncogenes regulate central aspects of cellular physiology such as cell proliferation and differentiation. The proto-oncogenes c-fos, c-fms and c-myc are thought to be involved in these processes. In this study the human myelomonoblast line THP-1 has been used to study monocytic differentiation in response to various cytokines and the phorbolester TPA. After treatment of THP-1 cells with Tumor Necrosis Factor (TNF)-alpha, Interleukin (IL-6) and TPA the cells became adherent, lost their division potential and expressed new surface structures associated with monocytic differentiation. The expression of cfos and c-fms transcripts was rapidly induced within 45 min by these agents and declined to undectable levels within 24 h. Exposure of THP-1 to TNF-alpha, IL-6 and TPA was associated with a rapid downregulation of c-myc expression, that returned to starting levels within 36 h. However, treatment of THP-1 with other cytokines including Granulocyte (G)-, Macrophage (M)-Granulocyte/Macrophage (GM)-Colony Stimulating Factor (CSF), Interleukin (IL)-3 and Interleukin (IL)-4 failed to result in monocytic differentiation. These data suggest that changes in c-fms, c-myc and c-fos expression may be related to induction of monocytic differentiation and that their appearance or downregulation can be induced by certain cytokines.