Introduction

Ivermectin, a macrocyclic lactone, is used orally or parenterally for the treatment of nematodes or ectoparasites in many animal species (^{Yazar, 2020}) and humans (^{Ashour, 2019}). It is used in the therapy of gastrointestinal, eye, and lung nematodes, filariasis and ectoparasites in sheep (Yazar, 2020). It can affect the immune system by affecting cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6 (^{Bekdur et al., 2018}), and immunoglobulins (^{Yan et al., 2011}). Interleukins can be proinflammatory or anti-inflammatory, depending on the role they play in inflammation. Interferon (IFN)-α, TNF-α, and IL-6 are proinflammatory cytokines, while IL-2 and IL-10 are anti-inflammatory cytokines. Interferons mainly show antiviral activity, TNF-α is an important mediator of acute infection, and IL-6 stimulates the synthesis of acute-phase proteins and immunoglobulins (^{Akdogan and Yontem, 2018}). Five different types of immunoglobulins are secreted by B lymphocytes. IgG is the most abundant immunoglobulin. IgM is synthesized in the acute phase of infections, after which it decreases and is replaced by IgG (^{Yilmaz and Akgul, 2014}). IgE is normally found at very low levels and is associated primarily with allergic reactions (^{Amarasekera, 2011}).

As ivermectin can stimulate the immune system (^{Blakley and Rousseaux, 1991}; ^{Omer et al., 2012}), it has been hypothesized that ivermectin administration to healthy sheep might affect specific immune system components such as cytokines and immunoglobulins. The aim of this study was to investigate possible short-term effects of ivermectin on cytokines (IFN-α, TNF-α, IL-2, IL-6, IL-10) and immunoglobulins (IgG, IgM, IgE) in healthy sheep.

Materials and Methods

Results

Cytokine and immunoglobulin levels are presented in Table 1 and 2, respectively. Significant fluctuations in IL-2 and IL-10, and a temporary increase in TNF-α and IgE levels were observed. However, no statistically significantly changes were observed in INF-α, IL-6, IgG, or IgM levels.

Discussion

In this study, the ivermectin administration protocol followed the common procedure reported in the scientific literature, using 0.2 mg/kg (SID, three days) in the therapy of trichuriasis (^{Ashour, 2019}). Ivermectin caused significant (p<0.05) fluctuations in IL-2 and IL-10 and a temporary increase (p<0.05) in TNF-α, which peaked at day 0.5 (Table 1). In cattle with papillomatosis, ivermectin administration resulted in a transient non-significant increase in TNF-α and IL-6 levels (^{Bekdur et al., 2018}). In an allergic asthma mouse model, ivermectin induced a decrease in IL-4, IL-5, and IL-13 (^{Yan et al., 2011}). When assessing the effect of ivermectin on cytokines secreted from lipopolysaccharide-induced macrophages in vitro, researchers reported that TNF-α and IL-1β were suppressed, IL-10 was increased, and IL-6 was not affected (^{Ci et al., 2009}). Similarly, after ivermectin was given to mice administered a lethal dose of lipopolysaccharide, it suppressed the production of TNF-α, IL-1β, and IL-6 (^{Zhang et al., 2008}). In an atopic dermatitis mouse model, ivermectin suppressed the production of several cytokines (^{Ventre et al., 2017}). In the present study, while ivermectin had no significant effect on IgG and IgM levels (p>0.05), it caused a temporary increase in IgE, which peaked on day 13 (Table 2). It also has been shown to reduce IgG and IgE levels and may exert antiallergic effects in an experimental asthma mouse model (Yan et al. 2011). In contrast, IgE -found at high levels in patients with hookworm-related cutaneous larva migrans- increased even more after ivermectin administration (^{Shimogawara et al., 2013}). It has been speculated that ivermectin may exert immunostimulatory effects via T lymphocytes (^{Blakley and Rousseaux, 1991}) or macrophages (^{Omer et al., 2012}), possibly providing an alternative approach in immunosuppressed patients. Ivermectin was shown not to be an immunostimulant in healthy dogs (^{Paradis, 1999}) and had no direct effect on the immune response in ectoparasite-infected rabbits and rats (^{Uhlir and Volf, 1992}). These results indicate that the effect of ivermectin on cytokines and immunoglobulins may vary by animal species and disease.

In conclusion, ivermectin at a dose of 0.2 mg/kg (SC, SID, 3 days) to healthy sheep caused changes in several serum cytokines (IL-2, IL-10, TNF-α) and IgE levels. However, these effects of ivermectin may vary according to the disease and animal species.