The herbal extract EPs\xae 7630 increases the antimicrobial airway defense through monocyte-dependent induction of IL-22 in T cells

Katrin Witte,Hans-Dieter Volk,Kerstin Wolk,Robert Sabat,Egon Koch

doi:10.1007/s00109-020-01970-3

Abstract

The phytotherapeutic compound EPs® 7630, an extract manufactured from Pelargonium sidoides roots, is frequently used for the treatment of airway infections. Nevertheless, the knowledge of the mode of action of EPs® 7630 is still sparse. Our study aimed at further elucidating the underlying pharmacological mechanisms by focusing on antimicrobial defense mechanisms of EPs® 7630. While investigating the influence of EPs® 7630 on lymphokine production by PBMCs, we found that EPs® 7630 is a novel inducer of IL-22 and IL-17. This cytokine-inducing effect was most pronounced for IL-22 and clearly dose-dependent starting from 1 μg/ml of the extract. Furthermore, EPs® 7630 pretreatment selectively enhanced the IL-22 and IL-17 production capacity of CD3/28-activated PBMCs while strongly limiting the IFN-γ production capacity of innate lymphoid cells. The relevance of EPs® 7630–induced IL-22 production was proven in vitro and in vivo, where IL-22 provoked a strong increase of the antimicrobial protein S100A9 in lung epithelial cells and pulmonary tissue, respectively. A detailed analysis of IL-22 induction modi revealed no direct influence of EPs® 7630 on the basal or anti-CD3/CD28 antibody-induced IL-22 production by CD4+ memory T cells. In fact, EPs® 7630–induced IL-22 production by CD4+ memory T cells was found to be essentially dependent on soluble mediators (IL-1/IL-23) as well as on direct cellular contact with monocytes. In summary, our study reveals a new immune-modulating function of EPs® 7630 that might confer IL-22 and IL-17-induced protection from bacterial airway infection.Key messagesEPs® 7630 selectively strengthens IL-22 and IL-17 production of memory T cells.EPs® 7630 limits the IFN-y production capacity of innate lymphoid cells.EPs® 7630–caused IL-22 production by T cells is essentially dependent on monocytes.IL-22 increase antimicrobial proteins (AMPs) in airway epithelium.EPs® 7630 might protect against airway infection by induction of AMP-inducers.

Highlights

Root preparations of Pelargonium sidoides, a medical herb belonging to the Geraniaceae family, have a long history of traditional use mainly for the treatment of diarrhea, intestinal colic, anemia, weakness, and complications related to dysentery and in rare cases for respiratory tract infections including tuberculosis in southern Africa [1]
EPs® 7630 provokes production of lymphocytic cytokines in human immune cells. Lymphocytes of both the adaptive (T cells) and innate immune system are known to play a crucial role in the antimicrobial host defense of epithelia through production of mediators, such as IL-22, IL-17, and a IL-22 protein [pg/ml]
peripheral blood mononuclear cells (PBMCs). a Human PBMCs were stimulated in a kinetic approach with 3 μg/ml EPs® 7630, 100 ng/ml LPS, or were left untreated as indicated. b Dose-response analysis was performed by treatment of human PBMCs with increasing concentrations (0–3 μg/ml, as indicated) of EPs® 7630

Summary

Introduction

Root preparations of Pelargonium sidoides, a medical herb belonging to the Geraniaceae family, have a long history of traditional use mainly for the treatment of diarrhea, intestinal colic, anemia, weakness, and complications related to dysentery and in rare cases for respiratory tract infections including tuberculosis in southern Africa [1]. More than 100 years ago, its commercialization started in the UK resulting in the development of the standardized ethanolic root extract EPs® 7630 (Umckaloabo®, ISO Arzneimittel, Ettlingen, Germany), which is approved for the treatment of acute bronchitis in Germany. In COPD patients, EPs® 7630 was observed to prolong the duration between exacerbations and to reduce their overall frequency [5]. Reduced asthma attack and cough frequency was reported for EPs® 7630–treated compared with untreated asthmatic children [6]. Pelargonium preparations were reported to strengthen the defense mechanisms of the body against different types of pathogens

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