Increased expression of CD25, CD83, and CD86, and secretion of IL-12, IL-23, and IL-10 by human dendritic cells incubated in the presence of Toll-like receptor 2 ligands and Giardia duodenalis

Abstract

BackgroundEffects of Giardia duodenalis on dendritic cell (DC) functions may contribute to the pathogenesis of chronic giardiasis. G. duodenalis lysate has been shown to inhibit the activation of murine DCs through the ligands of various Toll-like receptors (TLRs), including TLR2 and TLR4. Our study aimed at translating these findings to human DCs.FindingsAs described previously for murine DCs, also human DCs were only weakly activated by the parasite itself. LPS-stimulated DCs incubated in the presence of G. duodenalis lysate produced less IL-12/23p40 (p = 0.002), IL-12p70 (p = 0.011), and IL-23 (p = 0.004), but more IL-10 (p = 0.006) than cells incubated in the absence of the parasite. Concomitantly, the expression of CD25, CD83, CD86, and HLA-DR was reduced on G. duodenalis-incubated DCs as compared to control cells. In contrast, human DCs stimulated through TLR2 in combination with TLR1 or TLR6 and G. duodenalis lysate secreted significantly more IL-12/23p40 (p = 0.006), IL-23 (p = 0.002), and IL-10 (p = 0.014) than cells stimulated through TLR2 ligands alone. Ligands for TLR2/TLR1 or TLR2/TLR6 also induced enhanced extracellular expression of CD25, CD83, and CD86 (p < 0.05).ConclusionsIn contrast to murine DCs, human DCs incubated in the presence of G. duodenalis and stimulated through TLR2 show increased activation as compared to cells incubated in the absence of the parasite. Thus, TLR2 ligands, e.g., delivered by probiotic lactobacilli, might be beneficial in human giardiasis through an adjuvant effect on the induction of cellular immune responses against G. duodenalis.

The Intersection of Immune Responses, Microbiota, and Pathogenesis in Giardiasis

“…Total Giardia extract increased expression of the costimulatory molecules, CD80 and CD86, on murine bone marrow derived DCs, yet it did not invoke a strong cytokine response [80]. This weak cytokine response was also seen in human monocyte-derived DCs [81] exposed to Giardia . Interestingly, both studies [80, 81] showed that DC exposure to lipopolysaccharide (LPS) and Giardia resulted in an increase in IL-10 production; Kamda and Singer [80] further showed that blocking IL-10R and phosphoinositide-3 kinase (PI-3K) restores production of IL-12, which suggests that Giardia may activate PI-3K in DCs.…”

The Immunological Enigma of Human Giardiasis

“…However, G. duodenalis extracts alter the response of human MoDCs co-stimulated with known PRR-ligands such as some recognized by Toll like receptors (TLRs). TLR4 (lipopolysaccharide (LPS))-stimulated MoDCs in the presence of G. duodenalis extracts secreted lower levels of IL-12 and IL-23 and higher levels of IL-10 and reduced surface expression of CD25, CD83, CD86, and HLA-DR, while TLR2 ligand (Pam)-stimulated MoDCs increased all cytokine levels (IL-12, IL-23, IL-10) and surface markers indicating a modulatory effect on stimulated DCs [70]. A recent study in mice identified intestinal macrophages expressing arginase 1 and nitric oxide synthase 2 in the small intestine during G. duodenalis infection [71].…”

“…To study the response of DC upon stimulation with G. duodenalis products, monocyte-derived DCs (MoDC) have been generated from human blood. In congruence with the lack of inflammation in the gut, G. duodenalis trophozoites or trophozoites products activate cytokine/chemokine response or maturation of human (and mouse) dendritic cells only weakly if at all [69,70]. However, G. duodenalis extracts alter the response of human MoDCs co-stimulated with known PRR-ligands such as some recognized by Toll like receptors (TLRs).…”

Bioethics and Psoriasis

“…TNFα is the "prime" mode by which TLR2 destroys organisms. TLR2 also upregulates IL 17 and IL 12/23 [6,7]. The TNFα, IL 17 and IL 12/23 are all well-known cytokines involved in the pathogenesis of psoriatic lesions.…”