As it was established in our previous studies, the proteins of human serum γ-globulin fraction could interact with copper or zinc ions distributed in the periglobular space, form metal complexes, and become able to perform effector functions differing due to the conformational shifts from those mediated by them in native conformation of their Fc regions. In the present work we have evaluated ability of the γ-globulin metal complexes formed with copper or zinc ions in the conditions like to the physiological ones to induce production or to regulate induction in the culture of freshly isolated human peripheral blood cells (PBC) of granulocyte (G) and granulocyte-macrophage (GM) colony-stimulating factors (CSF) as well as of vascular endothelial growth factor (VEGF). The γ-globulin metal complexes formed with both copper and zinc ions were found to similarly reduce production of GM-CSF, G-CSF, and VEGF induced in normal human PBC cultures by the control γ-globulins or by copper and zinc ions used alone. In context of theory and practice of inflammation the properties of the γ-globulin metal complexes might impact the basic knowledge in search of novel approaches to anti-inflammatory drugs development.

Plasma γ-globulin fraction proteins, copper and zinc cations, and metal complexes of these cations and human serum γ-globulin induce the production of TNF-α by human blood cells. The protein modified by zinc cations is by 1.4-1.7 times more potent (p<0.001-0.01) than control γ-globulin in inducing the production of TNF-α, while metal complex formed by γ-globulin and copper is by 1.9-2.2 times more potent that the control protein (p<0.001). Under conditions of experimental induction, TNF-α is produced as a typical early response cytokine. During long-term incubation, copper cations lose the ability to induce TNF-α production, while in combination with γ-globulin these cations produce a synergistic effect with the control protein.

Plasma γ-globulin fraction proteins, copper cations, and metal complexes formed by copper cations with human serum γ-globulin induce the production of up to 4.0 ng/ml IL-8 by human blood cells. Protein modified by copper cations is 1.3-1.7-fold (p < 0.001-0.01) more potent than control γ-globulin and 1.3-fold (p < 0.001) more potent than copper cations alone. Analysis of the time course of IL-8 production demonstrated that IL-8 is produced as a prolonged or delayed response cytokine under conditions of this induction.

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