Activation Of Host Defense Mechanisms Research Articles

Chemical Mediators Released by Primary–Cultured Human Hepatic Macrophages in Patients With and Without Cirrhosis: A Study in Tumor–Bearing Patients

To elucidate the possible role of chemical mediators in modulating the host–defense activity of patients with cirrhosis, primary–cultured human hepatic macrophages (HHMΦ) were obtained from cirrhotic and noncirrhotic patients who received liver resections because of the presence of malignant liver tumors. The cirrhotic and noncirrhotic groups consisted of patients with similar malignancies: noncirrhotic patients had normal liver function and normal liver histology for nontumorous portions. The cultured HHMΦ were analyzed for their ability to release chemical mediators with specific activities in the host defense system. Dose–dependent increases in superoxide release, interleukin–1 (IL–1) release, and, within a relatively narrow range, prostaglandin–E2 (PGE2) release were observed in opsonized zymosan (oz)–stimulated HHMΦ derived from both cirrhotic and noncirrhotic patients. The release of O2– and PGE2 from HHMΦ derived from cirrhotic patients was significantly less than HHMΦ derived from noncirrhotic patients, whereas the release of IL–1 was significantly greater. Although, because of the limited sample availability, only tumor–bearing patients were studied, the mediator–releasing ability of HHMΦ derived from cirrhotic patients was significantly different from the ability of HHMΦ derived from noncirrhotic patients with similar malignancies. This phenomenon may be related to altered host defenses in patients with cirrhosis.

Chemical mediators released by primary-cultured human hepatic macrophages in patients with and without cirrhosis: A study in tumor-bearing patients

To elucidate the possible role of chemical mediators in modulating the host-defense activity of patients with cirrhosis, primary-cultured human hepatic macrophages (HHMphi) were obtained from cirrhotic and noncirrhotic patients who received liver resections because of the presence of malignant liver tumors. The cirrhotic and noncirrhotic groups consisted of patients with similar malignancies: noncirrhotic patients had normal liver function and normal liver histology for nontumorous portions. The cultured HHMphi were analyzed for their ability to release chemical mediators with specific activities in the host defense system. Dose-dependent increases in superoxide release, interleukin-1 (IL-1) release, and, within a relatively narrow range, prostaglandin-E2 (PGE2) release were observed in opsonized zymosan (oz)-stimulated HHMphi derived from both cirrhotic and noncirrhotic patients. The release of O2- and PGE2 from HHMphi derived from cirrhotic patients was significantly less than HHMphi derived from noncirrhotic patients, whereas the release of IL-1 was significantly greater. Although, because of the limited sample availability, only tumor-bearing patients were studied, the mediator-releasing ability of HHMphi derived from cirrhotic patients was significantly different from the ability of HHMphi derived from noncirrhotic patients with similar malignancies. This phenomenon may be related to altered host defenses in patients with cirrhosis. (Hepatology 1996 Jun;23(6):1353-8)

Cytokine secretion in acute shigellosis is correlated to disease activity and directed more to stool than to plasma.

Stool and plasma cytokine levels in 60 adults with acute shigellosis were studied by EIA at various intervals (0-45 days) after onset of diarrhea. Cytokine levels correlated with severity of disease. Significantly higher levels of proinflammatory cytokines peaked at onset of disease in stool of patients with severe disease (P < .05). In contrast, interferon-gamma (IFN-gamma) levels, depressed at disease onset, progressively increased during the convalescent stage. Concomitantly obtained plasma cytokine levels were 100 times lower than levels in stool. Controls in Shigella-endemic areas (n = 42) had persistently significantly higher levels of IFN-gamma and interleukin-1 receptor antagonist in both stool and plasma. The lack of host defense activity against shigellosis may be linked to delayed recovery of IFN-gamma. This cytokine may play an important role in elimination of the infection and development of immunity against shigellosis.

Influence of host defense activation on sleep in humans

Despite considerable progress in our understanding of the phenomenology of sleep and wakefulness, their regulation and peculiar functions are poorly understood. Recent animal research has revealed considerable evidence for interactions between host defense and sleep. Therefore, it has been hypothesized that host response mediators, mainly cytokines like interleukin-1 (IL-1), are involved in physiological sleep regulation. Furthermore, it has been suggested that sleep, and non rapid eye movement (NREM) sleep in particular, has an immuno-supportive function. In humans, sleep-host defense interactions are just starting to be understood. There is quite good evidence that some viral diseases cause excessive sleepiness. Other infectious diseases induce, however, serious disturbances of the distribution of sleep and wakefulness rather than excessive sleep. In addition, some disorders with excessive sleep, daytime fatigue or disturbed night sleep as prominent symptoms are thought to involve, at least in part, immuno-pathophysiological mechanisms. Experimental settings have only recently been used to elucidate host defense-sleep interactions in humans. The effects of endotoxin, a cell-wall lipopolysaccharide of gramnegative bacteria, on sleep have been tested in different settings in healthy volunteers. Endotoxin transiently suppresses rapid eye movement (REM) sleep independently of the time of the day of administration. Only low doses, given in the evening, promote NREM sleep. Electorencephalogram (EEG) power in higher frequency bands is enhanced during NREM sleep, whereas delta activity is not affected. In rats and rabbits, on the other hand, the effects of endotoxin and of the mediators of its activity on REM sleep are variable. Enhanced NREM sleep is a common finding and most pronounced during the active part of the nycthemeron and, in general, EEG delta activity is augmented. In view of these species differences, hypotheses regarding the underlying mechanisms and the biological significance of host defense-sleep interactions, primarily derived from the results of animal studies, may not entirely fit human physiology. They should therefore be re-evaluated and probably modified, through the use of additional experimental approaches in humans.

Factors involved in the down-regulation of cytochrome P450 during Listeria monocytogenes infection

The activation of host defense mechanisms has been shown to cause a depression in hepatic cytochrome P450-mediated metabolism in rodents and humans. In a previous study, it was demonstrated that the Gram-positive bacteria Listeria monocytogenes causes a down-regulation of hepatic cytochrome P450 and related substrate metabolism as a result of a pretranslational depression of apoprotein synthesis. The objectives of this study were to determine whether the effect of listeria on hepatocyte cytochrome P450 involves hepatic nonparenchymal cells and whether the hemolysin, secreted only by hemolytic forms of the bacteria, plays any part in mediating this effect. Total cytochrome P450 levels as well as ethoxyresorufin- O-dealkylase (EROD) and benzyloxyresorufin- O-dealkylase (BROD) activities were significantly reduced in hepatic microsomes isolated from mice infected in vivo for 48 h with 15U listeria, whereas the same dose of the avirulent non-hemolytic M3D strain had no effect. Listeria (15U) significantly depressed hepatocyte EROD and BROD activities after 24 h incubations with liver cell cultures containing hepatocytes and nonparenchymal cells, as the result of both a direct effect on the hepatocyte and an interaction of listeria with hepatic nonparenchymal cells. The M3D strain of listeria had no effect on cytochrome P-450-mediated metabolism in isolated cells, confirming that hemolysin is an essential component of the mechanism responsible for the down-regulation of cytochrome P450 during listeria infections.

Macrophage scavenger receptors.

Macrophage scavenger receptors are integral membrane proteins whose ability to bind and degrade modified LDL has implicated them in the process of atherosclerotic foam cell formation. Their ability to bind non-lipoprotein ligands suggests that they participate in other macrophage-associated host defense activities. Studies utilizing cloned native and mutant forms of the scavenger receptor have provided insights into the structural basis for their function.

Human microglial cell defense against Toxoplasma gondii. The role of cytokines.

Microglia may play an important role in host defense of the central nervous system against Toxoplasma gondii, and cytokines produced by these glial cells may participate in their antitoxoplasma activity. In our study, the antitoxoplasma activity of human fetal microglia was investigated. The RH strain of T. gondii multiplied readily in these glial cells. IFN-gamma/LPS-treated microglia limited (p < 0.01) T. gondii growth by reducing entry of this parasite rather than intracellular multiplication. More than 90% of the antitoxoplasma activity of activated microglia was blocked (p < 0.01) by neutralizing antibodies to TNF-alpha or IL-6 (but not to IL-1 or TGF-beta), suggesting that these proinflammatory cytokines play a role in the inhibitory process. Consistent with this hypothesis, treatment of microglia with TNF-alpha or IL-6 (in the presence or absence of IFN-gamma) inhibited (p < 0.01), in a dose-dependent manner, T. gondii growth. Inasmuch as NGMA did not affect cytokine-mediated antitoxoplasma activity of microglia, nitric oxide appears not to be involved in this host defense function of human fetal microglia. Results of our study suggest that the host defense activity of human microglia against T. gondii is dependent primarily on the activating properties of IFN-gamma, TNF-alpha, and IL-6.

Phagocytotic cells in the fish heart.

Comparatively little is known about host-defense activities in the fish heart. Investigations showed that intraperitoneally injected carbon particles are actively taken up by the cardiac endothelial cells of the medaka Oryzias latipes, but less so by those of the goldfish Carassius auratus and lemon tetra Hyphessobrycon pulchripinnis. (In vitro experiments confirmed these species differences in endocytic activities by these cells.) Electron microscopy revealed that endothelial cells of the medaka atrium have large cytoplasm with many organelles, and ingested carbon particles were observed within phagosomes of cardiac endothelial cells even at 4 degrees C. Phagocytic cells, which apparently reside in the heart, were found in all the species examined. These cells were located on the endothelial cells and developed cytoplasmic processes extending toward the heart lumen and/or the intercellular spaces of the endothelial cells. The heart with its resident phagocytes is proposed to function as a host defense organ--at least in certain fish species.

Seasonal variation in the function of blood monocytes obtained from healthy nonsmokers, asymptomatic smokers, and smokers with chronic bronchitis.

The present study focused on two questions: What effects do cigarette smoking and chronic bronchitis have on the function of the precursors of alveolar macrophages, the blood monocytes? Can seasonal variations affect the function of these cells? Phagocytic activity (the proportion of yeast-ingesting cells and the mean number of yeast particles per ingesting cell) and metabolism of arachidonic acid [secretion of prostaglandin E2 (PGE2) and leukotriene B4 (LTB4) in zymosan-stimulated cultures] were studied as markers of monocyte function during three seasons: spring (May-June), autumn (November-December), and winter (February). Smokers with chronic bronchitis (SCBs) and asymptomatic smokers (ASs) had a lower proportion (p < 0.05) of ingesting monocytes than healthy nonsmokers (HNSs) during spring, but not during the other two seasons. The secretion of PGE2 was highest during autumn and lowest during spring in the monocytes of all three groups. In autumn, LTB4 secretion was increased in the monocytes of HNSs (p < 0.05) but not in those of ASs and SCBs. LTB4 secretion was similar in all groups during the other two seasons. Cigarette smoking and chronic bronchitis seem to impair the function of monocytes and may thereby affect the systemic host defense activity. Cells collected during autumn were generally more active than those sampled in spring, indicating marked seasonal variation in the function of monocytes from all three groups.

Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins

Porcine leukocytes contained three homologous peptides, PG-1, 2 and 3, that manifested potent microbicidal activity against Escherichia coli, Listeria monocytogenes and Candida albicans in vitro. The peptides (‘protegrins’) were composed of 16 (PG-2) or 18 amino acid residues, and, like tachyplesins (broad-spectrum antibiotic peptides of horseshoe crab hemocytes), they contained two intramolecular cystine disulfide bonds. Considerably smaller than defensins, protegrins nevertheless showed substantial homology to them, especially to the ‘corticostatic’ rabbit defensin, NP-3a. The relatively simple structure of protegrins should provide useful prototypes for constructing congeners with selectively enhanced host defense activities.

Hepatic cytochrome P450 and related drug biotransformation during an outbreak of mouse hepatitis virus in a colony of Swiss BALB/c mice

Mouse hepatitis is a common highly infectious virus of the Coronaviridae family that commonly infects laboratory colonies of BALB/c mice. In a natural outbreak of this disease in our institution we demonstrated that mouse hepatitis virus appears to have little or no effect on the levels of cytochrome P450 or on the activities of ethoxyresorufin O-dealkylase and benzyloxy resorufin O-dealkylase in hepatic microsomes. Antibody titers for the virus were elevated in all mice tested and were negative in a control uninfected group. In a number of studies carried out over a period of months during the active outbreak we did not observe lower levels of cytochrome P450 in comparison with infectious free periods. Although the activation of host defence mechanisms and infections are well known to diminish the cytochrome P450 enzyme system in the liver, these results indicate that during a period of confirmed active infection with mouse hepatitis virus there was no evidence of an impairment in drug biotransformation enzymes.

Cell wall oligogalacturonides increase cytosolic free calcium in carrot protoplasts

ABSTRACT The mode of action of cell wall elicitors in the induction of various plant cell responses, such as the activation of host defence mechanisms, is unknown, but signal transduction through cytosolic free calcium ([Ca2+]i) has been suggested. This paper shows that polygalacturonic acid or oligogalacturonides cause a prolonged increase in [Ca2+]i of carrot protoplasts within 20 min of induction. Our data support the view that a special conformation of the oligogalacturonides possessing &amp;gt;9 residues is necessary to induce an elevation in [Ca2+]i. The localization of [Ca2+]i elevation around the periphery of protoplast cytoplasm and the inhibition of the response with verapamil suggest that exogenous Ca2+ is the major source for the rise in [Ca2+]i.

Host Defense Activity in Various Hosts: Human Neutrophil NADPH Oxidase Activity

The superoxide generation of neutrophil NADPH oxidase from healthy subjects, patients with respiratory infections, and patients receiving effective therapy with antibiotics or steroids was investigated. In young healthy nonsmokers the mean oxidase activity of neutrophils in women was significantly lower than that in men. In healthy women the mean oxidase activity was significantly lower in young nonsmokers than in young smokers or the elderly. In young nonsmokers, oxidase activity significantly increased during respiratory infections; however, in elderly nonsmokers, no significant increase in oxidase activity was observed during respiratory infections. The mean oxidase activity in patients receiving steroids was very low. In in vitro experiments using cell-free activation systems of NADPH oxidase, steroids were found to injure the membrane-bound components of the oxidase enzyme. These results suggest that decreased superoxide generation in patients receiving steroids may result from steroid-induced damage in the membrane-bound components of the NADPH oxidase system. The inhibitory effect of steroids on superoxide production may reduce bactericidal action of neutrophils, ie, one defense mechanism of the body against many kinds of pathogens. Therefore, long-term therapy with steroids in the elderly should be avoided at all costs.

Treatment of coxsackievirus B3 myocarditis by immunoactive peptide in an animal model

The effect of immunostimulant therapy on acute viral myocarditis, induced with coxsackievirus B3 (CB3), was investigated in C3H/He mice. Peritoneal exudate cells (PEC) or spleen cells (SC) from mice pretreated with a synthetic immunoactivating peptide FK565 significantly inhibited the multiplication of CB3 in C3H/He mouse embryo fibroblast cells compared with PEC or SC from nontreated mice in vitro (6.45 ± 0.20 log 10 PFU/ml; control: 6.85 ± 0.05, P < 0.05; 6.40 ± 0.07, control: 6.78 ± 0.07, P < 0.05, respectively), although FK565 did not inhibit viral replication directly. Mice were inoculated intraperitoneally with 3 × 10 5 plaque-forming units of CB3. FK565, 1 or 10 μg/kg, given intraperitoneally daily started on the same day of viral inoculation. To determine CB3 virus titer, mice were killed on Day 3. To study survival and myocardial histopathology, mice were killed on Day 20. Histopathological findings were scored on a scale of 0 to 4. FK565, 10 μg/kg/day, effectively inhibited myocardial viral replication (3.23 ± 0.42 log 10 PFU/mg, control: 3.71 ± 0.40, P < 0.05), reduced the cellular infiltration (1.3 ± 0.7, control: 2.5 ± 0.5, P < 0.05), myocardial necrosis (1.4 ± 0.9, control: 3.0 ± 0.6, P < 0.01), and calcification of the heart (1.0 ± 0.6, control: 2.5 ± 0.5, P < 0.01) and increased survival (60%, control: 30%, P < 0.05). The present study suggests that immunostimulant therapy improves the course of viral myocarditis during the viral-mediated phase. The inhibitory activity of FK565 seems to be due to the activation of host defense mechanisms.

Metchnikoff and the Origins of Immunology: From Metaphor to Theory

This elegant and scholarly work explores the contributions of Elie Metchnikoff to the development of modern immunology. The book was enlightening for me, because, although I am of Russian heritage and was an immunology fellow, I was not fully aware of the tremendous impact that Metchnikoff had on the field of immunology as we know it today. The lengthy but lively introduction includes a brief biography of the man who shared the Nobel Prize with Ehrlich in 1908. For Metchnikoff, science was religion, and he applied his basic biologic theories to his outlook on life in general. Interestingly, he published papers on psychological and sociological topics in addition to his important biologic works. The field of immunology arose in the 1880s from the converging arenas of microbiology, pathology, and comparative embryology. The basic concept of modern immunology, that of an active host defense afforded by cells of the phagocytic series,

Neurohumoral modulation of functional reserves and activity of host defenses.

Neurohumoral modulation of functional reserves and activity of host defenses.

Immunomodulatory Therapy With Thymopentin and Indomethacin

Prostaglandin E2 (PGE2)-mediated monocyte (M phi) suppressor activity and inadequate T-helper cell function represent the mechanistic keystones of trauma-induced impairment of cell-mediated immunity (CMI). In a prospective randomized trial, the immunorestorative potential of a combined therapy with the thymomimetic substance Thymopentin (TP-5; Timunox, Cilag GMBH, Sulzbach, FRG) and the cyclooxygenase inhibitor indomethacin (Indo) in 60 patients (mean age, 63 +/- 2 years) undergoing open heart surgery was studied. Perioperative immunologic screening was carried out on days -2, 3, 1, 5, and 7 and included the in vivo delayed type hypersensitivity (DTH) skin response, phenotyping for peripheral blood mononuclear cell (PBMC)-specific and nonspecific induction of lymphoproliferative responses, in vitro interleukin-2 (IL-2) synthesis, as well as the serum concentration of D-erythro-Neopterin (NPT) and of gamma interferon (gamma-IFN). The study protocol comprised three groups (n = 20): PA (Indo 150 mg administered intravenously on days 0 to 5), PB (TP-5 administered subcutaneously on days 0, 2, 4, and Indo), and PC (control). In contrast to PC, significant immunorestoration could be demonstrated in PB, as DTH scores on day 7, as well as proliferative responses in cell cultures were not depressed after operation (p less than 0.05). Cell-surface receptor expression for the CD3+, CD4+, and IL-2 receptor-positive (IL-2R+) lymphocyte subpopulations following surgery was reduced to 75% of baseline values in PC, while in PB, receptor protection for CD4+ and IL-2R+ subpopulations (more than 15% above baseline) was observed. Interleukin-2 synthesis (average baseline value, 0.7 + 0.08 U/mL) in cell cultures of PC was massively suppressed, with lymphokine concentrations in the supernatants never more than 0.27 +/- 0.05 U/mL. In PA cultures, IL-2 synthesis was impaired as well but not as precipitously as in PC. In contrast, in PB cultures, the average IL-2 production on consecutive postoperative days was never below baseline values. This study clearly demonstrates that the combined Indo/TP-5 therapy is superior to single Indo administration and can adequately preserve and/or restore intact M phi T-cell interaction and thus appears to be a feasible approach to maintain normal host defense activity in traumatized individuals.

The role of inflammatory mediators in the pathogenesis of periodontal disease

The role of bacteria in the initiation of periodontitis is well-documented and the end result, destruction of the alveolar bone and periodontal connective tissue, is readily observed; but the events occurring between these two points in time remain obscure and are the focus of this paper. Bacteria induce tissue destruction indirectly by activating host defense cells, which in turn produce and release mediators that stimulate the effectors of connective tissue breakdown. Components of microbial plaque have the capacity to induce the initial infiltrate of inflammatory cells including lymphocytes, macrophages, and PMNs. Microbial components, especially lipopolysaccharide (LPS), have the capacity to activate macrophages to synthesize and secrete a wide array of molecules including the cytokines interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-alpha), prostaglandins, especially PGE2, and hydrolytic enzymes. Likewise, bacterial substances activate T lymphocytes and they produce IL-1 and lymphotoxin (LT), a molecule having properties very similar to TNF-alpha. These cytokines manifest potent proinflammatory and catabolic activities, and play key roles in periodontal tissue breakdown. They induce fibroblasts and macrophages to produce neutral metalloproteinases such as procollagenase and prostromelysin, the serine proteinase urokinase-type plasminogen activator (u-PA), tissue inhibitor of metalloproteinase (TIMP), and prostaglandins, u-PA converts plasminogen into plasmin, which can activate neutral metalloproteinase proenzymes, and these enzymes degrade the extracellular matrix components. TIMP inactivates the active enzymes and thereby blocks further tissue degradation. Several amplification and suppression mechanisms are involved in the process. While LPS activates macrophages to produce IL-1, IL-1 is autostimulatory and can therefore amplify and perpetuate its own production. Interferon-gamma (INF-gamma) suppresses autostimulation, but it enhances LPS-induced IL-1 production. PGE2 exerts a control over the whole process by suppressing production of both IL-1 and TNF-alpha. Furthermore, the activated cells produce an IL-1 receptor antagonist that binds to the IL-1 receptor but does not induce the biologic consequences of IL-1 binding. Other cytokines such as transforming growth factor-beta (TGF-beta) suppress production of metalloproteinases and u-PA. Thus the progression and extent of tissue degradation is likely to be determined in major part by relative concentrations and half-life of IL-1, TNF-alpha, and related cytokines, competing molecules such as the IL-1 receptor antagonist, and suppressive molecules such as TGF-beta and PGE2. These molecules control levels of latent and active metalloproteinase and u-PA, and the availability and concentration of TIMP determines the extent and duration of degradative activity.

Oxidative modification of glutamine synthetase: covalent and conformational changes which control susceptibility to proteolysis.

Mixed function oxidation of proteins has been implicated in a variety of physiologic and pathologic processes, including intracellular protein turnover, host defense activities, oxygen toxicity, and the aging process. Many key enzymes are susceptible to oxidative modification, usually with loss of catalytic activity.1 Glutamine synthetase from Escherichia coli is oxidatively modified by a number of enzymic and non-enzymic mixed function oxidation systems.2,3 To understand the effects of oxidative modification, we have studied the covalent and non-covalent changes in glutamine synthetase which occur upon oxidative modification. Protein of varying extent of modification was prepared by timed exposure to a model system consisting of ascorbate, iron, and molecular oxygen.1,4 These modified proteins were analyzed for several covalent and conformational changes. We were particularly interested in identifying changes which correlate with increased susceptibility to proteolysis by a novel high molecular weight protease purified from rat liver.KeywordsGlutamine SynthetaseHistidine ResidueSedimentation VelocityOxidative ModificationCation Binding SiteThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Prolongation of survival of mice bearing the Eb and ESb lymphoma by treatment with interferon inducers alone or in combination with Corynebacterium parvum.

The objective of this study was to evaluate if pretreatment with Corynebacterium parvum (C. parvum) augments the effects of interferon (IFN) inducers on survival of DBA/2 mice transplanted with two syngeneic lymphoma variants, the low metastatic Eb and the high metastatic ESb tumor. The involvement of IFN in the treatment effects was investigated. As inducers of IFN-alpha/beta Newcastle disease virus (NDV), polyinosinic-polycytidylic acid (polyI:polyC), and 10-carboxymethyl-9-acridanone (CMA) were injected i.p. at the site of tumor transplantation. The Eb tumor was found to be sensitive to the antiproliferative action of IFN-alpha/beta in vitro. In vivo single injections of each of the inducers retarded growth of the Eb tumor. In C. parvum-pretreated mice the effects of the inducers on survival were markedly increased. There was a correlation between prolonged survival and local IFN levels in response to polyI:polyC or CMA but not upon NDV. Injections of each of the inducers increased cytotoxicity of peritoneal exudate cells against the Eb tumor cells in vitro especially when mice were pretreated with C. parvum. Although other mechanisms cannot be excluded IFN-mediated activation of host defence and also direct antiproliferative effects of endogenously produced IFN seem to be involved in the antitumor effects by these IFN inducers in the Eb model. In the ESb tumor model irrespective of additional pretreatment with C. parvum survival was only slightly prolonged by the treatments and endogenous IFN induction did not result in any real benefit for the animals. When compared with Eb cells the ESb cells were less sensitive to the antiproliferative action of IFN-alpha/beta in vitro and less sensitive to in vitro cytotoxicity by the host cells. Although other mechanisms may additionally be active in vivo the different susceptibility of the Eb and ESb tumor cells to the direct and indirect actions of IFN seems to contribute to the different responsiveness of these tumor cell lines to the treatments with IFN inducers.