Contents - Previous - Next

6. Cytokine regulation: Natural antagonists and biological modulators

Native interleukin-1 inhibitors have been known to exist for over a decade now (LARRICK, 1989), when a small 23-25 kd protein was found in the urine of patients with monocytic leukemia and associated with blockade of IL-1 in a number of cell assays. This inhibitor was subsequently found to block the binding of IL-1 to its receptor (SECKINGER et al., 1987), and was named the interleukin-1 receptor antagonist (IL-1ra). It has now been purified from adherent monocytes and the gene has been cloned (AREND et al., 1989; EISENBERG et al., 1990). The properties of this molecule are just beginning to be examined in detail, however it is already established that it is regulated independently of IL-1 (POUTSIAKA et al., 1991).

Culture conditions for human peripheral blood mononuclear cells (stationary vs rocking) and nature of the stimulus employed are reported to influence the two molecules differentially. For example, IgG or GM-CSF induced the IL-1ra but not IL-1, whereas preventing cell contact by rocking the cells led to diminished Il-1ra but not IL-1 production in the presence of LPS. In addition to its effects in vitro in blocking IL-1 activity, in at least one experiment, administration of exogenous IL-1ra to rabbits with septic shock due to Escherichia coli infection significantly blunted the biological responses (WAKABAYASHI et al., 1991).

The availability of the IL-1ra has reopened some of the newly established dogma to experimental approaches not possible before. For example, the role of TNF in pathogenesis of shock syndrome seemed to be well established when baboons subjected to E. coli sepsis were protected by monoclonal antibody to TNF (FONG et al., 1989). However, the levels of IL-1 were also elevated in this model, and coupled with the protective effect of IL-1ra in a similar infection model in rabbits, these data suggest that TNF may act via IL-1 in the induction of shock. In turn, however, blockade of IL-1 by IL-1ra leads to the inhibition of IL-1 induced IL-1, TNF, and IL-6 synthesis. Thus, the single specific inhibitory molecule has profound effects on a larger range of cytokines because of the networking pathways among these mediators, and as is generally the case in cytokine biology, it is not easy to decide which molecule is doing what.

While further studies of the in vivo effects of IL-1ra are ongoing (DINARELLO and THOMPSON, 1991), it is interesting to speculate whether or not the favorable responses to IgG infusion in certain disease states such as Kawasaki syndrome (NEWBURGER et al., 1986) or ITP (NEWLAND et al., 1983), could be related to induction of the inhibitor protein.

Similar natural inhibitors of TNF have been isolated from human urine obtained from febrile patients (SECKINGER, ISAAZ and DAYER, 1989), from pathogenic fluids (DAYER, 1991), and from tissue culture cells (KOHNO et al., 1990). These molecules appeared to act by binding to the ligand, rather than the receptor as in the case of the IL-1ra. When it was found that the inhibitor appeared on the surface of cells activated with phytohemagglutinin and IL-2, the concept was put forward that these inhibitors represented soluble forms of the TNF receptor (SECKINGER et al., 1990). The extracellular domain of TNF receptor fragments cloned from U-937 human histiocytic lymphoma cell lines resembled not only the TNF inhibitor, but also the extracellular domain of nerve growth factor receptor, suggesting that all are members of a family of polypeptide hormone receptors (DAYER, 1991).

In contrast to the lack of IL-1ra activity in normal plasma, the TNF inhibitor activity was detectable under basal conditions (SPINAS et al., 1990). A bolus of E. coli LPS given to normal human volunteers induced IL-1ra and further increased the TNF inhibitor activity. Thus, both of these natural cytokine inhibitors share the property of being induced by the same stimulus up-regulating the ligand, indicating that the inhibitors may play a role in cytokine homeostasis. In moving towards producing a potent TNF inhibitor for use in humans, a fusion protein has been prepared containing the extracellular domain of the human 55 kd TNF receptor linked to the Fc and hinge region of mouse IgG1 heavy chain and expressed in CHO cells (PEPPEL, CRAWFORD and BEUTLER, 1991).

7. The future

Where are these developments in understanding nutrition-infection-immune system interactions taking us? While it may be begging the question, it is still necessary to propose new research to more fully unravel the cytokine network and its regulation of nutritional status in infection and immune system activation. At the same time, the nature of these potent mediators as double-edged swords, suggests that care must be taken in answering the many questions remaining. While several specific topics can readily be proposed, it is important to emphasize a guiding theme to direct these studies. The most important theme at this time is to know what happens in vivo, and further, we need to know what happens at the tissue level, and not the level of the circulation. These research needs can be divided into five major areas (TRACEY and CERAMI, 1992).

Methods to assess cytokines in vivo. These methods must allow the detection of transcriptional and translational events. and they must be able to detect cleavage products of various cytokines as well as biological inhibitors.

Tissue/cell-specific responses. The in vitro data demonstrate how multiple cytokines can interact, synergize, or inhibit one another. This now must be studied in vivo, and we need to be asking questions about the impact of sequential administration and dosing of cytokines, including when several cytokines are given together or simulatenously by different routes or doses.

Genetic issues. Are there HLA or other gene linkages that affect individuals and their cytokine response? It is of interest that the genetic defect in the NOD diabetic mouse maps to the same region of the chromosome as the Lsh/Ity/Bcg genes (which govern resistance to intracellular pathogens, Leishmania, Salmonella and Mycobacterium) and the IL-1 receptor gene. Is this by chance or is it a real linkage?

Nutrition. Are there threshold levels of protein and energy which affect cytokine priming or the response of either transcription or translation to second signals? What impact does protein-energy malnutrition have on the production of cytokines themselves, or on lymphoid cell activation markers in response to other signals?

Specific cytokine inhibitors or receptor antagonists. These studies are currently receiving great attention, as there is considerable clinical potential because, at least the IL-1ra, is safely given in large amounts to humans. These molecules need to be studied with a view towards both the immunological and the nutritional consequences of infection in order to develop appropriately targeted interventions.

When these data become available, we will be in a position to really address the questions initially posed which are, today, still unanswered. Here, then, lies the frontier in nutrition-infection-immune system interactions.


AREND, W.P., JOSLIN, F.G., THOMPSON, R.C. et al.: An IL-I inhibitor from human monocytes: Production and characterization of biological properties. J. Immunol., 143, 1851-1858 (1989).

BARRY, W.S., PIERCE, N.F.: Protein depreviation causes reversible impairment of mucosal immune response to cholera toxoid/toxin in rat gut. Nature, 281, 64-65 (1979).

BEACH, R.S., GERSHWIN, M.E., HURLEY, L.S.: Nutritional factors and autoimmunity. III. Zinc deprivation versus restricted food intake in MLR/J mice - the distinction between interacting dietary influences. J. Immunol., 129, 2682-2692 (1982).

REACH, R.S., GERSHWIN, M.E., HURLEY, L.S.: Persistent immunological consequences of gestational zinc deprivation. Am. J. Clin. Nutr., 38, 579-590 (1983).

BEISEL, W.R.: Metabolic effects of infection. Prog. Food Nutr. Sci., 8, 43-75 (1984).

BENSI, G., RAUGEI, G., PALLA, E. et al.: Human interleukin 1 beta gene. Gene, 52, 95-101 (1987)

BEUTLER, B., MAHONEY, J., LETRANG, N., PEKALA, CERAMI, A.: Purification of cachectin, a lipoprotein lipase-suppressing horomone secreted by endotoxin-induced RAW 264.7 cells. J. Exp. Med., 161, 984-995 (1985a).

BEUTLER, B., GREENWALD, D., HOLMES, J.D., CHANG, M., PAN, Y.-C.E., MATHISON, J., ULEVITCH, R., CERAMI, A.: Identity of tumor necrosis factor and the macrophage-secreted factor cachetin. Nature, 316, 552-554 (1985b).

BOMSZTYK, K., SIMS, J.E., STANTON, T.H. et al., Evidence for different interleukin 1 receptors in murine B- and T-cell lines. Proc. Natl. Acad. Sci. (USA), 86, 8034-8038 (1989).

BURKHOLDER, W.J., SWECKER, W.S., Jr.: Nutritional influences on immunity. Sem. Vet. Med. Surg., 5, 154-166 (1990).

CHANDRA, R.K.: Antibody formation in first and second generation offspring of nutritionally deprived rats. Science, 190, 289-290 (1975).

CHIZZONITE, R., TRUITT, T., KILIAN, P.L. et al.: Two high-affinity interleukin 1 receptors represent separate gene produces. Proc. Natl. Acad. Sci. (USA), 86, 8029-8033 (1989).

DAYER, J.M.: Chronic inflammatory joint diseases: natural inhibitors of interleukin 1 and tumor necrosis factor alpha. J. Rheumatol., 27, 71-75 (1991).

DINARELLO, C.A.: Interleukin-1. Rev. Infect. Dis., 6, 51-95 (1984).

DINARELLO, C.A.: Interleukin-1 and its biologically related cytokines. Adv. Immunol., 44, 153-205 (1989).

DINARELLO, C.A.: Interleukin-1. In: The Cytokine Handbook, pp. 47-82. Academic Press, New York, NY, 1991.

DINARELLO, C.A., RENFER, L., WOLFF, S.M.: Human leukocytic pyrogen: Purification and development of a radioimmunoassay. Proc. Natl. Acad. Sci. (USA), 74, 4624-4627 (1977).

DINARELLO, C.A., BISHAI, I., ROSSENWASSER, L.J., COCEANI, E: The influence of lipoxygenase inhibitors on the in vitro production of human leukocytic pyrogen and lymphocyte activating factor (interleukin 1). Int. J. Immunopharmacol., 6, 43-50 (1984)

DINARELLO, C.A., CANNON, J.G., WOLFF, S.M. et al.,: Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1. J. Exp. Med., 163, 1433-1450 (1986).

DINARELLO, C.A., CANNON, J.G., MANCILLA, J. et al.,: Interleukin-6 as an endogenous pyrogen: induction of prostaglandin E2 in brain but not in peripheral blood mononuclear cells. Brain Res., 562, 199-206 (1991).

DINARELLO, C.A., THOMPSON, R.C.: Blocking IL-I: interleukin 1 receptor antagonist in vivo and in vitro. Immunol. Today, 12, 404-410 (1991).

DuBOIS, E.F.: The Mechanism of Heat LOSS and Temperature Regulation. Stanford University Press, Palo Alto, CA, 1937.

EISENBERG, S.P., EVANS, R.J., AREND, W.P. et al.,: Primary structure and functional expression from complementary DNA of a human interleukin 1 receptor antagonist. Nature, 343, 341-346 (1990).

ERICKSON, K.L.: Dietary fat modulation of immune response. Int. J. Immunopharmacol., 8, 529-543 (1983).

FEINGOLD, K.R., SOWED, M., SERIO, M.K. et al.: Multiple cytokines stimulate hepatic lipid synthesis in vivo. Endocrinology, 125, 267-274 (1989).

FEINGOLD, K.R., DOERRLER, W., DINARELLO, C.A.: Stimulation of lipolysis in cultured fat cells by tumor necrosis factor, interleukin 1, and the interferons is blocked by inhibition of prostaglandin synthesis. Endocrinology, 130, 10-16 (1992).

FERNANDES, G., YUNIS, E.J., MIRANDA, M. et al.: Nutritional inhibition of genetically determined renal disease and autoimmunity with prolongation of life in kd/kd mice. Proc. Natl. Acad. Sci. (USA), 75, 2888-2892 (1978).

FONG, Y., TRACEY, K.J., MOLDAWER, L.L. et al.: Antibodies to cachectin/tumor necrosis factor reduce interleukin 1 b and interleukin 6 appearance during lethal bacteremia. J. Exp. Med., 170,1627-1633 (1989).

FURUTANI, Y., NOTAKE, M., FUKUI, T. et al., Complete nucleotide sequence of the gene for human interleukin 1 alpha. Nucleic Acids Res., 14, 3167-3179 (1986).

GEBRASE-DeLIMA, M., LIU, R.K., CHENEY, K.E. et al., Immune function and survival in a long-lived mouse strain subjected to undernutrition. Gerontology, 21, 184-202 (1975)

GRUNFELD, C., VERDIER, J.A., NEESE, R. et al., Mechanisms by which tumor necrosis factor stimulates hepatic fatty acid synthesis in vivo. J. Lipid Res., 29, 1327-1335 (1988).

GRUNFELD, C., WILKING, H., NEESE, R. et al., Persistence of the hypertriglycedemic effect of tumor necrosis factor despite development of tachyphylaxis to its anorectic/cachectic effects in rats. J. Cancer Res., 49, 2554-2560 (1989a).

GRUNFELD, C., GUILLE, R., MOSER, A.H. et al., Effect of tumor necrosis factor administration in vivo on lipoprotein lipase activity in various tissues of the rat. J. Lipid Res., 30, 579-585 (1989b).

GRUNFELD, C., ADI, S., SOUED, M. et al., Search for mediators of the lipogenic effects of tumor necrosis factor: potential role for interleukin 6. Cancer Res., 50, 4233-4238 (1990).

HARRIS, H.W., GRUNFELD, C., FEINGOLD, K.R. et al.: Human very low density lipoproteins and chylomicrons can protect against endotoxin-induced death in mice. J. Clin. Invest., 86, 696-702 (1990).

HOLTMANN, H., WALLACH, D.: Down regulation of the receptors for tumor necrosis factor by interleukin 1 and 4 beta phenol-12-myristate-13-acetate. J. Immunol., 139, 1161-1167 (1987).

HWANG, D.: Essential fatty acids and immune response. FASEB Journal, 3, 2052-2061 (1989).

ISHII, E., OHGA, S., UEDA, K.: Tumor necrosis factor and fever at diagnosis in children with solid tumors. Pediatr. Hematol. Oncol., 7, 253-257 (1990).

JOSE, D.G., STUTMAN, O., GOOD, R.A.: Long term effects on immune function of early nutritional deprivation. Nature, 241, 447-454 (1973).

KAWAKAMI, M., PEKALA, P.H., LANE, M.D., CERAMI, A.: Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin-induced mediator from exudate cells. Proc. Natl. Acad. Sci. (USA), 79, 912-916 (1982).

KEUSCH, G.T.: Nutrition as a determinant of host response to infection and the metabolic sequellae of infectious diseases. In: Seminars in Infectious Diseases, Vol. 2, pp. 265 - 303, L. WEINSTEIN, B. FIELD (Eds.). Grune & Stratton, 1979.

KEUSCH, G.T.: Micronutrients and susceptibility to infection. Ann. N.Y. Acad. Sci., 587, 181-188 (1990a).

KEUSCH, G.T.: Malnutrition, infection, and immune function. In: The Malnourished Child. R.M. SUSKIND, L. LEWINTER-SUSKIND, L. (Eds.). Nestlé Nutrition Workshop Series, Vol. 19, pp. 37-55, Raven Press, NY, 1990b.

KEUSCH, G.T.: Malnutrition and the thymus gland. In: Nutrient Regulation of Immune Response in Human Development and Disease, pp. 283-299, S. CUNNINGHAM-RUNDLES (Ed.). Dekker, New York, NY, 1992.

KEUSCH, G.T., WILSON, C., WAKSAL, S.D.: Nutrition host defense and the lymphoid system. In: Advances in Host Defense Mechanisms, pp. 275-359, J.I. GALLIN, A.S. FAUCI (Eds.). Raven Press, New York, NY, 1983.

KEUSCH, G.T., FARTHING, M.J.G.: Nutrition and infection. Annul Rev. Nutr., 6, 131-154 (1986).

KLUGER, M.J.: Fever: role of pyrogens and cryogens. Physiol. Rev., 71, 93-127 (1991).

KNUDSEN, P.J., DINARELLO, C.A., STROM, T.B.: Glucocorticoids inhibit transcriptional and post-transcriptional expression of interleukin-1 in U937 cells. J. Immunol., 139, 4129-4134 (1987).

KOHNO, T., BREWER, M.T., BAKER, S.L. et al.: A second tumor necrosis factor receptor gene product can shed a naturally occurring tumor necrosis factor inhibitor. Proc. Natl. Acad. Sci. (USA), 87, 8331-8335 (1990).

KRAMER, T.R., GOOD, R.A.: Increased in vitro cell-mediated immunity in protein-malnourished guinea pigs. Clin. Immunol. Immunopathol., 11, 212-228 (1978).

LARRICK, J.W.: Native interleukin 1 inhibitors. Immunol. Today, 10, 61-66 (1989).

LONG, C.L.: Energy balance and carbohydrate metabolism in infection and sepsis;. Am. J. Clin. Nutr., 30, 1301-1310 (1977).

MASCIOLI, E.A., LEADER, L., FLORES, E. et al., Enhanced survival to endotoxin in guinea pigs fed IV fish oil emulsion. Lipids, 23, 623-625 (1988).

MATHUR, M., RAMALINGASWAMI, V., DEO, M.G.: Influences of protein deficiency on 19S antibody-forming cells in rats and mice. J. Nutr., 102, 841-846 (1972).

MATSUSHIMA, K., YODOI, J., TAGAYA, Y. et al: Down-regulation of interleukin125 1 receptor expression by IL-1 and fate of internalized I-labeled IL-1 b in a human large granular lyumphocyte cell line. J. Immunol., 137, 3183-3188 (1986).

NATHAN, C., SPORN, M.: Cytokines in context. J. Cell. Biol., 113, 981-986 (1991).

NEWBURGER, J.W., TAKAHASHI, M., BURNS, J.C. et al., The treatment of Kawasaki syndrome with intravenous gamma globulin. N. Engl. J. Med., 315, 341-347 (1986).

NEWLAND, A.C., TRELEAVEN, J.G., MINCHINTON, R.M. et al., High-dose intravenous IgG in adults with autoimmune thrombo-cytopenia. Lancet, 1, 84-87 (1983).

PEKALA, P.H., LANE, M.D., CERAMI, A.: Lipoprotein lipase suppression in 3T3-L1 cells by an endotoxin induced mediator from exudate cells. Proc. Natl. Acad. Sci. (USA), 79, 912-916 (1982).

PEPPEL, K., CRAWFORD, D., BEUTLER, B.: A tumor necrosis factor (TNF) receptor-IgG heavy chain chimeric protein as a bivalent antagonist of TNF activity. J. Exp. Med., 174, 1483-1489 (1991).

POUTSIAKA, D.D., CLARK, B.D., VANNIER, E. et al.: Production of interleukin 1 receptor antagonist and interleukin 1 b by peripheral blood mononuclear cells is differentially regulated. Blood, 78, 1275-1281 (1991).

PRICE, P., BELL, R.G.: Factors determining the effects of chronic protein-deficiency on antibody responses to sheep red blood cells and Brucella abortus vaccine in mice. Aust. J. Exp. Biol. Med. Sci., 55, 59-78 (1973).

REDDY, P.G., FREY, R.A.: Nutritional modulation of immunity in domestic food animals. Adv. Vet. Sci. Comp. Med., 35, 255-281 (1990).

REINHARDT, M.C., STUART, N.W.: Antibody affinity and clearance function studies in high and low antibody affinity mice. The effect of protein deficiency. Immunology, 38, 735-739 (1979).

RING, J. SEIFERT, J., MERTIN, J. et al.: Prolongation of skin allografts in rats treated with linolenic acid. Lancet, 2, (1331), (1974).

SCHINDLER, R., CLARK, B.D., DINARELLO, C.A.: Dissociation between interleukin-1 mRNA and protein synthesis in human peripheral blood mononuclear cells. J. Biol. Chem., 265, 10232-10237 (1990).

SCRIMSHAW, N.S., TAYLOR, C.E., GORDON, J.E.: Interactions of nutrition and infection. Am. J. Med. Sci., 237, 367-403 (1959).

SCRIMSHAW, N.S., TAYLOR, C.E., GORDON, J.E.: Interaction of nutrition and infection. WHO Monograph Series 57. World Health Organization, Geneva, 1968.

SECKINGER, P., ISAAZ, S., DAYER, J.M.: Purification and biologic characterization of a specific tumor necrosis factor alpha inhibitor. J. Biol. Chem., 264, 11966-11973 (1989).

SECKINGER, P., ZHANG, J.H., HAUPTMANN, B. et al.: Characterization of a tumor necrosis factor alpha (TNF alpha) inhibitor: evidence of immunological cross-reactivity with the TNF receptor. Proc. Natl. Acad. Sci. (USA), 87, 5188-5192 (1990).

SECKINGER, P., LOWENTHAL, J.W., WILLIAMSON, K. et al.: A urine inhibitor of interleukin I activity that blocks ligand binding. J. Immunol., 139, 1546-1549 (1987).

SIRKO, S., SCHINDLER, R., DOYLE, M.J., WEISMAN, S.M., DINARELLO, C.A.: Transcription, translation and secretion of interleukin 1 and tumor necrosis factor: Effects of tebufelone, a dual cyclooxygenase/5-lipoxygenase inhibitor. Eur. J. Immunol., 21, 243-250 (1990).

SPINAS, G.A., BLOESCH, D., KAUFMANN, M.T. et al.: Induction of plasma inhibitors of interleukin 1 and TNG-alpha activity by endotoxin administration to normal humans. Am. J. Physiol., 259, R993-R997 (1990).

SUTTLES, J., GIRI, J.G., MIZEL, S.B.: IL-I secretion by macrophages. Enhancement of IL-I secretion and processing by calcium ionophores. J. Immunol., 144, 175-182 (1990).

TRACEY, K.J., LOWRY, S.F.: The role of cytokine mediators in septic shock. Adv. Surg., 23, 21-56 (1990).

TRACEY, K.J., CERAMI, A.: Tumor necrosis factor (TNF) and regulation of metabolism in infection: role of systemic versis tissue levels. Proc. Soc Exp. Biol. Med., 200, 233-233 (1992).

WAKABAYASHI, G., GELFAND, J.A., BURKE, J.F. et al.: A specific receptor antagonist for interleukin 1 prevents Escherichia coli induced shock. FASEB J., 5, 338-343 (1991).

WALFORD, R.L., LIU, E.R., GEBRASE-DeLIMA, M. et al.: Long term dietary restriction and immune function in mice. Response to sheep red blood cells and to mitogen agents. Mech. Ageing Dev., 2, 447-454 (1973).

WEINDRUCH, R., WALFORD, R.L.: Dietary restriction in mice beginning at one year of age: effect on life span and spontaneous cancer incidence. Science, 215, 1415-1418 (1982).

WEINDRUCH, R., GOTTESMAN, S.R.S., WALFORD, R.L.: Modification of age-related immune decline in mice dietarily restricted from or after midadulthood. Proc. Natl. Acad. Sci. (USA), 79, 898-893 (1982).

WEINDRUCH, R., DEVENS, E.H., RAFF, H.V. et al.: Influence of dietary restriction and aging on natural killer cell activity in mice. J. Immunol., 130, 993-996 (1983).

ZIEGLER, E.J.: Tumor necrosis factor in humans. N. Engl. J. Med., 318, 1535-1555 (1988).

Contents - Previous - Next