Cytokines, Acute‐Phase Proteins, and Hormones

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Abstract
The cytokine network is a homeostatic system that has to be perceived in an analogous fashion to the acid/base equilibrium. The level of any cytokine in biological fluids can be interpreted correctly only by taking into account the levels of other synergistic cytokines, of their respective inhibitors, and of each cytokine receptor. Due to their potent activities in many different processes (including cell growth and differentiation, development, and repair processes leading to the restoration of homeostasis), the cytokine activities have to be tightly controlled by natural inhibitory mechanisms. Since one of the main functions of cytokines is to mediate interactions between the immune and inflammatory system, it is thought that chronic immuno-inflammatory diseases might be caused in part by the uncontrolled production of cytokines. Depending on the stage of inflammation or the biological effect determined, the same cytokine might be pro- or anti-inflammatory. This applies, for instance, to IL-4, IL-10, and TGFβ. An important mechanism that triggers the production of pro-inflammatory cytokines in chronic inflammatory diseases is the direct cellular contact between stimulated T cells and monocyte-macrophages. This mechanism is blocked at the systemic level by the “negative” acute-phase protein apolipoprotein A-I (apo A-I). The levels of expression of cytokines and cytokine inhibitors and acute-phase proteins are ruled by hormones. Estrogens as well as androgens inhibit the production of IL-1β and TNF-α on monocyte-macrophages. However, androgens antagonize estrogen stimulatory effects on apo A-I synthesis by the liver. Other studies suggest that estradiol is more inhibitory to Thl cytokines (e.g., IFNγ, IL-2), while testosterone is inhibitory to Th2 cytokines (e.g., IL-4). Cytokines also control the axis of the hypothalamic-hypophyseal-adrenal glands as well as the sexual hormones. The discrepancy between studies would suggest that the mechanisms are different in physiological and pathophysiological conditions.