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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.

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