TRENDS

More insights into the complex physiology of TNF Salem Chouaib, Didier Branellec and Wim A. Buurman

Despite the enormous amount of data that has been generated, the molecular basis of TNF action remains largely unresolved. Regarding the TNF-mediated cytotoxic reaction, the existence of a membranebound TNF-like molecule expressed on some killer cells was reported to play a role in cytolysis against some target cells (K. Okumura, Juntendo Univ.) and ADP ribosylation of a 90kDa protein appears to be involved in the initial stage of the cytotoxic reaction (S. Agarwal, Univ. of Pittsburgh). The Fas antigen, which is expressed on lymphocytes, may also transduce a cytolytic signal (I.B. Owen Schaub, Univ. Texas) and anti-Fas antibodies induce a cell killing effect on tumor cell lines if used in such a way that they crosslink Fas antigen. TNF receptors (TNF-Rs) cocap with Fas antigen crosslinked by anti-Fas antibody, which suggests a tight relation between the two molecules (S. Yonehara, Tokyo Metropolitan Inst.). N. Matthews (Univ. of Wales) reported functional differences between TNF-susceptible and TNFresistant variants of tumor cell lines. Two parameters appear to be involved in the control of TNF resistance and susceptibility, namely the glycosylation of a 105 kDa cell surface protein lysosome-associated membrane protein 1 (LAMP-l) and the number and distribution of acid vesicles. Studies using a subtraction technique adapted to identify TNFsusceptibility-related genes suggest that cytochrome c oxidase subunit gene expression is critical in TNF susceptibility (T. Kinebuchi, Juntendo Univ.). TNF receptors and TNF-binding protein From data on the physiology and structure of TNF receptors, it has become clear that there are two TNF

Tumor necrosis factor (TNF), a multifactorial cytokine involved in a plethora of cell regulatory and differentiative processes, was the subject of a recent conference*. It is perhaps best known as a major player in the pathophysiology of numerous diseases but TNF clearly has many beneficial effects and is considered to be a promising therapeutic agent.

which share no apparent homology with the known TNF receptors.

receptors (with molecular masses of 55 and 75 kDa). These possess markedly different intracellular regions, suggesting alternative modes in signalling and different function. Both receptors appear to occur in soluble form (D. Wallach, Weizmann Inst.; I. Olsson, Univ. of Lund; W. Lesslauer, Hoffman-La Roche, Basel). These soluble TNF receptors are present at surprisingly high concentrations in the plasma of normal healthy individuals (14ngml -t) and in pathological situations, such as inflammatory disorders and renal failure, even higher concentrations are observed. The function of this large pool of soluble TNF receptors was the subject of considerable discussion. A dual role, first as a means to absorb and inactivate TNF spilling out of localized inflammatory processes and second as an important slow release reservoir that could function to maintain a low level of biologically active available TNF, was considered to be most likely. The rapid shedding of soluble TNF receptors in response to TNF release may serve as a feedback mechanism, reducing the immediate availability of TNF and, presumably, prolonging its effects. Although it is known that TNF and lymphotoxin (LT) share common receptors, K. Hirano (Univ. of Tokyo) reported the purification of (60 and 65 kDa) TNF-binding proteins,

The cytokine network The concept that cytokines do not work individually but form a network of interacting signals with considerable overlapping activity continues to gain support. An interesting example of how the network performs has been obtained from in vitro and in vivo studies that suggest that lL-8 may mediate some of the inflammatory responses to TNF and interleukin 1 (lL-1) (K. Matsushima, Kanazawa Univ.): TNF induces IL-8 mRNA expression in human astrocytoma cell lines, perhaps reflecting a role for IL-8 in brain inflammatory lesions. Information on IL-8 action in vivo and an assessment of its therapeutic potential are awaited. The molecular basis of TNF-induced IL-8 gene expression was also discussed and appeared to require NF-KB- and NF-IL-6-binding motifs in the IL-8 gene promoter. An important role for IL-6 in inflammation, resulting in the induction of acute phase proteins in hepatocytes, also involves NF-IL-6 binding to the gene promoter as reported by T. Kishimoto (Osaka Univ.) in his overview on IL-6 signal transduction. In fa.ct, co-expression of NF-KB and CCAAT enhancer binding protein (C/EBP)-Iike nuclear factors (NFIL-6) appears to be a common feature in the regulation of the inflammatory response by IL-1, TNF and IL-6. Regulation of gene expression by TNF was also studied by J. Vilcek and co-workers (New York Univ.) using a differential screening strategy which has led to the isolation of eight TNF-induced sequence genes including the IL-8 gene.

*The Third International Conferenceon Tumor Necrosis Factor and Related Cytokines was held in Makuhari, Chiba, Japan on 21-25 November 1990.

TNF and disease The positive protective effects of TNF in inflammatory disease were confirmed in studies in which mice

© 1991, ElsevierSciencePublishers Ltd, UK. 0167-4919/91/$02.00

Immunology Today

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TRENDS were subjected to cecal ligation and puncture (P. Krammer, Heidelberg). With respect to TNF in human immunodeficiency virus (H1V) infection, the selective killing by TNF of HIV-infected cells could be considered as a positive effect of the cytokine. However, because TNF enhances viral replication through the induction of transcriptional factors of NK-KB type, it was suggested that TNF may be a major factor in progression of the disease. On the basis of these observations, the combination of zidovudine (AZT) to inhibit HIV replication and TNF to kill HIV-infected cells is being used as a therapeutic approach by N. Kobayashi (Tamaguchi Univ.). TNF release after HIV infection is accompanied by a decreased level of glutathione. L. Herzenberg (Stanford Univ.) reported that the restoration of glutathione levels by N-acetylcysteine (NAC) is associated with an inhibition of TNFinduced HIV replication through inhibition of NF-KB activation, and may therefore be used for slowing the progression of acquired immune deficiency syndrome (AIDS). C. Grunfeld (Univ. of California) proposed that TNF has a protective effect against endotoxin by enhancing lipogenesis, leading to a futile cycle of fatty acids. The enhanced uptake of fatty acids by hepatocytes that have absorbed endotoxin reduces the known toxic effect of endotoxin, by preventing uptake by monocytic cells. The involvement of TNF in pathology was further demonstrated in a study showing the essential role of the human T-cell leukemia virus 1 (HTLV-1) Tax gene in induction of LT mRNA expression via activation of NF-KB. The use of HTLV-I-long terminal repeat (LTR)-Tax transgenic mice model (N.H. Ruddle, Yale Univ.),

which exhibits extremely high bone turnover, provides new insights into the skeletal abnormalities observed in human HTLV-1 infection and related diseases. The immunoregulatory effect of TNF in some immunopathological diseases was demonstrated by J. Satoh (Tohoku Univ.), who pointed out that the inhibition of the development of autoimmune diabetes in nonobese diabetic (NOD) mice and BB rats could be achieved by in vivo administration of TNF. D. Mizuno and colleagues (Teikyo Univ.) called attention to the general concept that, via endogenous TNF, the homeostatic condition in patients with diseases can be improved; they supported this idea by showing that endotoxin could protect against autoimmune diseases in rodents. Furthermore, it was reported that lipopolysaccharide (LPS), isolated from wheat, which can be administered in various ways, may induce recovery from various disease states, such as arthritis and arteriosclerosis. Clinical applications D.R. Spriggs (Univ. of Wisconsin) gave an overview of phase II clinical trials that have been performed using a variety of recombinant TNF preparations over the last five years by different groups. A consensus has emerged from these studies that the anti-tumor potency of TNF used in systemic administration is disappointing, as reported by T. Taguchi (Osaka Univ.), R. Engelhardt (Max Planck Inst.) and others. This was based on an impressive collection of phase II trials using pulsed TNF infusions into patients with breast cancer, advanced colorectal, gastric and renal carcinoma which were reported and continuous i.v. infusions, preferred on the basis of the short

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TNF plasma life. Similar patterns of toxicity, severely limiting the TNF doses administered in humans, were observed using both methods. In an attempt to enhance the therapeutic index of TNF, two strategies were addressed during this conference that are based on more accurate schedules of administration and on combinations of TNF with other therapeutic agents. Using intratumoral administration of TNF for malignant skin cancer, Taguchi obtained interesting results and further confirmed the efficacy of local TNF versus systemic treatment. The use of TNF treatment in conjunction with other agents was also addressed by D.R. Spriggs who reported promising observations in IL-2 bolus injection combined with continuous TNF infusion into patients with non small cell lung cancer. TNF has been used as an adjuvant cytokine to chemotherapy with topoisomerase inhibitors. To limit the side effects of administered high TNF doses, R. Engelhardt (Albert-Ludwigs Univ.) and Mizuno based their strategy on the triggering of endogenous TNF production. By using EET (exogenous--endogenous therapy), indications for clinical efficacy were reported by Mizuno's group. W. Fiers et al. (Ghent) reported interesting data on TNF and lithium synergy during cell killing and presented some preclinical data showing the beneficial effect of TNF-induced tolerization on the anti-tumor potency of TNF and the limitation of this cytokine's side effects.

Salem Cbouaib and Didier Branellec are at the Laboratoire d'Immunologie UA 1156, lnstitut Gustave Roussy, Villejuif F-94805, France; and Wire Buurman is at tbe Dept of Surgery, Biomedical Center, University of Liraburg, Maastricbt, The Netherlands.

Immunology Today

* The B-cell antigen receptor complex * Cytokines in invertebrates * T-cell memory * Epitopic dominance

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More insights into the complex physiology of TNF.

Tumor necrosis factor (TNF), a multifactorial cytokine involved in a plethora of cell regulatory and differentiative processes, was the subject of a r...
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