INFLUENCE OF CYTOKINES ON MACROPHAGE TOLERANCE TO LIPOPOLYSACCHARIDE

Abstract

Relevance. Macrophages have great importance in the functioning of the immune system, being important participants in innate immunity. They are capable of both directly and indirectly fighting pathogens by regulating the work of surrounding cells through biologically active substances. In response to various stimuli, macrophages can switch from a basal state to a pro- or anti-inflammatory state, polarizing into the M1 or M2 phenotype. M1 macrophages have a pro-inflammatory phenotype, where macrophages are activated under the influence of lipopolysaccharide of the cell wall of gram-negative bacteria or some pro-inflammatory cytokines. M2 macrophages acquire an anti-inflammatory phenotype upon activation of some immune response receptors (Fcγ and TLR), cytokines IL-4, IL-13, IL-10 and other stimuli. Macrophages are also capable of weakening their immune response depending on the duration and/or frequency of the inflammatory signal and forming tolerance to it. Of particular importance is tolerance to bacterial lipopolysaccharide, during which macrophages acquire refractoriness to repeated stimulation compared to the primary one, producing fewer cytokines and chemokines.

Aim. In our study, we assessed the role of cytokines and chemokines CCL2, CXCL1, CXCL9, CXCL12, IL-1-beta, IL-4, IL-6, IL-7, IL-8, IL-15, IL-22, TNF-α on the immune response of macrophages to lipopolysaccharide and the formation of tolerance.

Materials and methods. Primary monocytes were obtained from venous blood of healthy donors. E. Coli lipopolysaccharide was used to stimulate monocytes and differentiated macrophages.

Results. We have shown that pre-treatment of primary human macrophages with recombinant cytokines IL-4 and TNF-α enhances the inflammatory response to repeated stimulation with lipopolysaccharide, i.e. weakens the development of tolerance. This effect was expressed in the increased production of cytokines - TNF-α, IL-6, IL-10 and chemokine IL-8 for recombinant IL-4 and TNF-α for recombinant TNF-α. At the same time, recombinant IL-4 was also able to enhance the inflammatory signal of macrophages upon a single stimulation with lipopolysaccharide, increasing the secretion of TNF-α and IL-8.

Conclusion. Thus, we have shown that some cytokines can affect the tolerance of macrophages to lipopolysaccharide. This phenomenon may involve the transition of macrophages from one polarization to another or to an intermediate form. Modulation of the phenotype and immune response of macrophages opens the way to the creation of new therapeutic approaches to inflammatory diseases, in the pathogenesis of which the development of tolerance to lipopolysaccharide plays a significant role - such as sepsis and atherosclerosis.