Manganous superoxide dismutase (MnSOD) scavenges potentially toxic superoxide radicals produced in the mitochondria. Tumor necrosis factor-alpha (TNF-alpha) was found to induce the messenger RNA for MnSOD, but not the mRNAs for other antioxidant or mitochondrial enzymes tested. The increase in MnSOD mRNA occurred rapidly and was blocked by actinomycin D, but not by cycloheximide. Induction of MnSOD mRNA was also observed with TNF-beta, interleukin-1 alpha (IL-1 alpha), and IL-1 beta but not with other cytokines or agents tested. TNF-alpha induced MnSOD mRNA in all cell lines and normal cells examined in vitro and in various organs of mice in vivo. These effects of TNF-alpha and IL-1 on target cells may contribute to their reported protective activity against radiation as well as their ability to induce resistance to cell killing induced by the combination of TNF-alpha and cycloheximide.

https://science.sciencemag.org/content/sci/242/4880/941.full.pdf

Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism.

In the present study we searched for restriction fragment length polymorphisms (RFLP) in the human interleukin-1 beta (IL-1 beta) gene and for correlations to monocyte (Mo) function in non-related healthy donors and insulin-dependent diabetic patients. We demonstrated a diallelic polymorphism with the restriction enzyme TaqI consisting of fragments of 9.4 kb and 13.4 kb. No differences in allele or genotype frequencies of this RFLP were observed between randomly selected controls and randomly selected patients with insulin-dependent diabetes mellitus (IDDM). However, when analysing IDDM patients negative for HLA-DR3 and -DR4, our data demonstrate that the 13.4 kb allele is more frequent in this group compared to a matched control group. The functional impact of this RFLP was studied by analysing in vitro stimulated Mo IL-1 beta response. An IL-1 beta allele dosage effect on secretory capacity was observed after LPS-stimulation: 13.4/13.4 kb homozygous individuals secreted significantly more IL-1 beta than 9.4/13.4 kb heterozygous individuals, who secreted significantly more than 9.4/9.4 kb homozygous individuals. Analyses of supernatants from LPS-stimulated Mo cultures from individuals with each TaqI IL-1 beta genotype revealed no differences in the mouse thymocyte co-stimulatory assay when compared on a molar basis, indicating that the TaqI polymorphism gave rise only to quantitative differences in expression levels and probably not to a mutant IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)

A Taql polymorphism in the human interleukin-1β (IL-1β) gene correlates with IL-1β secretion in vitro

Formerly called IFN-gamma-inducing factor, IL-18 is the new name of a novel cytokine that plays an important role in the TH1 response, primarily by its ability to induce IFN-gamma production in T cells and natural killer cells. Mice deficient in IL-18 have suppressed IFN-gamma production despite the presence of IL-12. IL-18 is related to the IL-1 family in terms of both structure and function. In terms of structure, IL-18 and IL-1beta share significant primary amino acid sequences and are similarly folded as all-beta pleated sheet molecules. Also similar to IL-1beta, IL-18 is synthesized as a biologically inactive precursor molecule lacking a signal peptide. Studies have shown that similar to the IL-1beta precursor, the IL-18 precursor requires cleavage into an active, mature molecule by the intracellular cysteine protease called IL-1beta-converting enzyme (ICE), which is also known as caspase-1. Therefore inhibitors of ICE activity may limit the biologic activity of IL-18 and may be useful as TH1 immunosuppressive agents. The activity of mature IL-18 is closely related to that of IL-1. IL-18 induces gene expression and synthesis of TNF, IL-1, Fas ligand, and several chemokines. The activity of IL-18 is by means of a signaling chain of a putative IL-18 receptor (IL-18R) complex. This IL-18R complex is made up of a binding chain termed IL-18Ralpha, a member of the IL-lR family previously identified as the IL-1R-related protein (IL-1Rrp), and a signaling chain, the IL-18Rbeta, also a member of the IL-1R family. The IL-18R complex recruits IL-1R-activating kinase and TNF receptor-associated factor-6, which phosphorylates nuclear factor kappaB (NFkappaB)-inducing kinase with subsequent activation of NFkappaB. Thus on the basis of primary structure, 3-dimensional structure, receptor family, signal transduction pathways, and biologic effects of IL-18 appear to place this cytokine in the IL-1 family. Similar to IL-1, IL-18 participates in both innate and acquired immunity.

IL-18: A TH1-inducing, proinflammatory cytokine and new member of the IL-1 family.

Multiple sclerosis (MS) brain tissue, spleen, and PBMC were studied using immunocytochemistry and FACS for immunoreactivity for lymphotoxin (LT) and TNF. Both cytokines were identified in acute and chronic active MS lesions but were absent from chronic silent lesions. LT was associated with CD3+ lymphocytes and Leu-M5+ microglia cells at the lesion edge and to a lesser extent, in adjacent white matter. TNF was associated with astrocytes in all areas of the lesion, and with foamy macrophages in the center of the active lesion. In acute lesions, immunoreactivity for TNF in endothelial cells was noted at the lesion edge. No LT or TNF reactivity was detected in Alzheimer's or Parkinson's disease brain tissues but was present at lower levels in central nervous system (CNS) tissue from other inflammatory conditions, except for adrenoleucodystrophy which displayed high levels of LT in microglia. No increase in LT and TNF reactivity was detected in spleen and PBMC of MS patients suggesting specific reactivity within the CNS. These results indicate that LT and TNF may be involved in the immunopathogenesis of MS, and can be detected in both inflammatory cells and cells endogenous to the CNS.

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Identification of lymphotoxin and tumor necrosis factor in multiple sclerosis lesions.

Article de synthese sur la pathogenie du diabete insulinodependant chez l'homme, le rat BB et la souris NOD, presente sous la forme d'une serie de questions concernant les processus genetiques et autoimmuns qui conduisent au diabete insulinodependant et des reponses actuelles a ces questions

Type-I Diabetes: A Chronic Autoimmune Disease of Human, Mouse, and Rat

An assay was developed to detect the cytotoxic effects of cytokines on rat pancreatic islet cells in monolayer culture. Cell lysis was detected by a 51Cr-release assay after 4 days of incubation with various cytokines. When tested alone, murine (rat and mouse) interferon-gamma (mIFN-gamma) produced a small dose-dependent lysis of islet cells; human IFN-gamma, mouse IFN-alpha/beta, interleukins 1 and 2 (IL-1 and IL-2), tumor necrosis factor (TNF), and lymphotoxin (LT) were inactive. When added together, the following combinations of cytokines showed synergistic cytotoxic effects: TNF (or LT) plus IL-1, TNF (or LT) plus mIFN-gamma, and IL-1 plus mIFN-gamma. These results indicate that the cytokine products of mononuclear cells of the immune system, IFN-gamma, TNF, LT, and IL-1 have strong synergistic cytotoxic effects on islet cells and therefore may act as direct chemical mediators of islet beta-cell destruction in type I (insulin-dependent) diabetes.

https://diabetes.diabetesjournals.org/content/diabetes/37/1/133.full.pdf

Destruction of Rat Islet Cell Monolayers by Cytokines: Synergistic Interactions of Interferon-γ, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1

Recent observations suggest a role for interleukin-1 (IL-1), a polypeptide product of macrophage/monocytic cells, in the immune-mediated destruction of pancreatic islet beta-cells observed in type 1 diabetes. In this study, we investigated the effects of IL-1 on both alpha- and beta-cell secretory functions in rat islet cell monolayer cultures. Insulin release was 97% inhibited after 6 h of incubation in RPMI-1640 medium (11 mM glucose) containing 1 U/ml IL-1 and 96% inhibited after 24 h of incubation in medium containing 0.1 U/ml IL-1. The cell content of insulin in the monolayers was decreased by 66% (P less than 0.01) after 4 days of incubation in 10 U/ml IL-1; however, after a further 8-day incubation in IL-1-free medium, cell insulin content recovered fully. In contrast, cell glucagon content was decreased by 77% (P less than 0.001) after 4 days of incubation in 10 U/ml IL-1 and did not recover after a further 8-day incubation in IL-1-free medium. After an 18-h preincubation in medium with 0.1 and 1 U/ml IL-1, insulin release responses to 16.7 mM glucose were abolished in 4-h incubations, whereas responses to 0.1 mM 3-isobutyl-1-methylxanthine were normal, and after a further 2 and 5 days of incubation in IL-1-free medium, insulin responses to 16.7 mM glucose recovered fully. Similarly, the inhibitory effect of 16.7 mM glucose on glucagon release was lost after an 18-h preincubation in 0.1 and 1 U/ml IL-1, and did not recover fully after 2 and 5 days in IL-1-free medium, whereas the stimulatory effect of 3-isobutyl-1-methylxanthine on glucagon release was not affected by IL-1. We conclude that 1) IL-1 inhibits glucose-dependent and not cAMP-dependent mechanisms of insulin and glucagon release; 2) inhibition of glucose-stimulated insulin release by IL-1 is reversible, whereas the effect on glucose-modulated glucagon release is not; and 3) IL-1 causes a reversible decrease in the insulin content of islet cells and an irreversible decrease in glucagon content. These actions of IL-1 do not appear to account for the beta-cell-specific destruction of islets characteristic of type 1 diabetes.

Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures.

Arachidonic acid metabolites (eicosanoids) have been implicated in mediating actions of cytokines in different tissues. In this study, we tested inhibitors of arachidonate metabolism for possible protection against the toxic effects of the cytokine combination of tumor necrosis factor (TNF, 100 U/ml) and interferon-γ (IFN-γ, 100 U/ml) in rat islet cell monolayer cultures, using a 51Cr release cytotoxicity assay to measure islet cell lysis (% 51Cr release). The toxic effect of TNF/IFN-γ (26.6 ± 3.7%) was inhibited partially by both a cyclooxygenase inhibitor, indomethacin and a lipoxygenase inhibitor, nordihydroguaiaretic acid (NDGA), and combination of maximally effective concentrations of Indo and NDGA (30 μM) produced further protection against TNF/IFN-γ-induced lysis (3.5 ± 0.9%). Also, the combined cyclo/lipoxygenase inhibitors, oxyphenbutazone and eicosa 5,8,11,14 tetrynoic acid, as well as the phospholipase A2 inhibitor, bromophenacyl bromide, significantly inhibited the cytotoxic effect of TNF/IFN-...

Cytotoxic Effects of Cytokines on Islet β-Cells: Evidence for Involvement of Eicosanoids*

A woman in complete remission from acute myeloblastic leukemia developed thrombotic thrombocytopenic purpura (TTP) subsequent to the third intensive consolidation cycle of cytosine arabinoside and daunorubicin chemotherapy. The constellation of clinical manifestations indicative of TTP were recognized only in retrospect, as they were initially attributed to more usual complications of bone marrow-ablative chemotherapy. The manifestations, probably fueled by numerous red cell and platelet transfusions, increased at the time of recovery of hematopoiesis. At postmortem examination, characteristic microvascular lesions were found in most organs. Similar thrombotic microangiopathy has been described with mitomycin-based chemotherapy regimens and with the combination of cisplatin, vinblastine, and bleomycin. Successful management of this serious complication of chemotherapy requires increased awareness and earlier recognition.

Hernan Baquerizo

Papers

Destruction of Rat Islet Cell Monolayers by Cytokines: Synergistic Interactions of Interferon-γ, Tumor Necrosis Factor, Lymphotoxin, and Interleukin 1

Interleukin-1 inhibits glucose-modulated insulin and glucagon secretion in rat islet monolayer cultures.

Cytotoxic Effects of Cytokines on Islet β-Cells: Evidence for Involvement of Eicosanoids*

Thrombotic thrombocytopenic purpura subsequent to acute myelogenous leukemia chemotherapy

Interferon-gamma sensitizes rat pancreatic islet cells to lysis by cytokines and cytotoxic cells