Cyto- and chemokines play a central role in immunoregulatory and inflammatory processes. Neutralizing antibodies for single proinflammatory cytokines have developed into powerful therapeutic strategies for several autoimmune diseases. Considering the redundancy of cyto- and chemokine functions, network rather than single target approaches may support the development of more targeted therapies. Phytopharmaceuticals, common adjuvant therapies, are cyto- and chemokine modulators, but are not systematically investigated. This work explored the in vitro modulation of cyto- and chemokine networks (CCN) of clinically established phytopharmaceuticals alone or in combination under non-inflammatory and inflammatory conditions for potential co-medication strategies. Human skinfibroblasts were treated with standardized extracts (E) of Populus tremula L., Solidago virgaurea L., Fraxinus excelsior L., the combined multiextract mixture STW1 or the reference drug acetyl salicyclic acid (ASA), alone or with lipopolysaccharides (LPS). CCN-profiles were determined in cell lysates by proteome profiler. Cell culture medium was investigated for IL-6 (ELISA). RNA gene-expression profiling was undertaken. P. tremula E and ASA increased cellular IL-8 and IL-10; S. virgaurea E modulated Groa, IL-1a, IL-10 and IL-15. F. excelsior decreased IL-1a and IL-15. The mixture of the three E - STW1 - modulated IL-1a, IL-3 and TNF-ß. LPS stimulation increased cellular Groa, IL-8, MCP-1 and RANTES and IL-6 secretion into the media. Except for F. excelsior, none of the single extracts reversed LPS-induced rises of cytokines. STW1 inhibited IL-1a, Groα, IL-8, and MCP-1. IL-6–secretion was reduced by STW1 and ASA. Gene expression profiles supported non-additive CCN-profiles. Salicylate and polyphenol based phytopharmaceuticals modulate specific cyto- and chemokine networks rather than inhibit single pro-inflammatory cytokines. Pro- and anti-inflammatory cytokine responses adapt to anti-inflammatory responses after LPS-stimulation. A simultaneous activation of pro- and anti-inflammatory cytokines might improve the immunological reactivity status of a cell.
[1] Ulrich-Merzenich G, Hartbrod F, Koptina A, Müller J, Kelber O, Zeitler H. Salicylate-based phytopharmaceuticals induce adaptive cytokine and chemokine network responses in human fibroblast cultures. Phytomedicine 2017;34:202-21