Pseurotin D inhibits delayed type IV hypersensitivity response

Dysregulated control of the immune system has major health consequences and is behind the development of numerous diseases including various autoimmune and allergic diseases that are on the rise in industrialized countries [1]. Exaggerated immune system responses can be triggered by the interaction with specific antigens that function as allergens and are referred to as hypersensitivities [2]. The immune system mechanisms that are responsible for delayed-type hypersensitivity play a crucial role in the body's fight against various intracellular pathogens such as mycobacteria and fungi [2]. However, a failure of their proper function among susceptible individuals leads to the development of type IV hypersensitivity disorder, often called delayed-type hypersensitivity (DTH), manifesting mostly as allergic reactions on skin. In general, DTH is primarily a T helper (Th) 1 cell-mediated immune response [3]. During the experimental induction of DTH in mice, two important phases are recognized. The first is the afferent or sensitization phase, where the mouse is exposed subcutaneously to a specific allergen that is classically emulsified in mineral oil. The consequent inflammatory reaction to the antigen typically peaks after 48 h. The second, efferent phase typically begins 5–12 days after sensitization. During the efferent phases, animals are again exposed to the allergen using dermal paw-pad sensitization, which results in the relocation of allergen-specific T cells into exposed tissue followed by the production of pro-inflammatory and DTH-mediating cytokines. The DTH response is evaluated 24 h after the second challenge [3].

Pharmacological targeting of the pathological dysregulation of immune system is the basis for a wide range of therapeutic applications [4,5]. Small organic molecules isolated from fungi represent highly attractive compounds that have a potential to modify cellular processes by affecting specific signaling pathways. A particularly interesting group of such fungal secondary metabolites are pseurotins, ergot-like alkaloids containing a 1-oxa-7-azaspiro [4,4]non-2-ene-4,6-dione core, that comprise a family with over twenty-five members including pseurotin A (Ps.A), pseurotin D (Ps.D), azaspirene, and synerazol [[6], [7], [8], [9]]. First, Ps.A was isolated from the fermentation broth of the fungi Pseudeurotium ovalis Stolk (Ascomycetes) [10]. Pseurotins are also produced by Aspergillus fumigatus (e.g. Ps.A, 8- O-demethylpseurotin A, Ps.D, F1/F2, 11- O-methylpseurotin A, and synerazol), by Neosartorya sp. (azaspirene), and Penicillium strains (Ps.A) [11].

Pseurotins have interesting biological activities. In addition to their antifungal and antibiotic activities [12], pseurotins were shown to modulate cell differentiation [13], to possess anti-angiogenic activity, to inhibit endothelial cell migration [[14], [15], [16]], to induce apoptosis through the targeting of redox sensitive pathways in human lymphoid leukemia cells [17], and to regulate enzymes of cellular metabolism [18]. Importantly, interesting effects were observed on the function of the immune system. In our previous studies, we observed that Ps.A and Ps.D significantly inhibited the proliferation of murine macrophages, which was accompanied by downregulation of the expressions of cyclins and mitochondrial respiration via the inhibition of particular signal transducers and activators of transcription (STAT) and mitogen-activated protein kinase signaling pathways [19]. Further, Ps.D significantly inhibited the activation of both human T helper and T cytotoxic cells complemented by the inhibition of tumor necrosis factor (TNF-α) production without significant acute toxic effects [20]. Interestingly, both Ps.A and Ps.D and a collection of fully synthetic pseurotin analogs were shown to inhibit immunoglobulin (Ig) E production and the proliferation of B cells [21]. Moreover, synerazol and 10-deoxypseurotin A also showed IgE inhibitory activity and immunosuppressive activity inhibiting mixed lymphocyte reaction [22]. Remarkably, Ps.D was revealed to be more potent than the most studied pseurotin, Ps.A [19,21]. Overall, pseurotins can be viewed as natural products with the potential to specifically affect immune system functions.

The aim of this study was to evaluate the potential of Ps.D to reduce the delay type IV hypersensitivity response in a mouse model of ovalbumin (OVA)-mediated DTH and clarify the mechanism of action on immune cells. The main focus was on Th cell and B cell response, since our previously published data suggested the significant potential of natural pseurotins as well as pseurotin analogs to affect these immune cells [19,21].

留言 (0)

沒有登入
gif