Abstract
BackgroundThe immune modulating potential of IL-35 in multiple human disorders has been reported. Consequent upon the recognition of inflammatory cytokine activation and its preponderance for mediating pathology during malaria infection, the study aimed to characterize the expression and functional contribution(s) of IL-35 in Plasmodium berghei (strain ANKA) infected mice.MethodsPlasmodium berghei infection in male ICR mice was used as the rodent model of choice. The time course of IL-35 expression in the systemic circulation and tissues of P. berghei infected mice as well as their healthy control counterparts was assessed by enzyme linked immunosorbent assay and immunohistochemistry respectively. The effect of modulating IL-35 by recombinant IL-35 protein or neutralizing anti-Epstein-Barr virus-induced gene 3 antibody on the cytokine environment during P. berghei infection was assessed by flow cytometry. Furthermore, the influence of modulating IL-35 on histopathological hallmarks of malaria and disease progression was evaluated.ResultsInterleukin-35 was significantly up regulated in serum and tissues of P. berghei infected mice and correlated with parasitaemia. Neutralization of IL-35 significantly enhanced the release of IFN-γ, decreased the expression of IL-6 and decreased parasitaemia patency. Neutralization of IL-35 was also associated with a tendency towards increased survival as well as the absence of pathological features associated with malaria infection unlike recombinant IL-35 protein administration which sustained a normal course of infection and unfavourable malaria associated histological outcomes in P. berghei infected mice.ConclusionThese results indicate the involvement of IL-35 in P. berghei induced malaria infection. IL-35 neutralization strategies may represent viable therapeutic modalities beneficial for the resolution of malaria infection.
Highlights
The immune modulating potential of interleukin 35 (IL-35) in multiple human disorders has been reported
IL‐35 was up regulated in serum and correlated with parasitaemia levels during P. berghei infection Assessment of IL-35 concentration at different time intervals during the course of P. berghei infection by enzyme linked immunosorbent assay (ELISA) revealed that serum IL-35 concentration during the course of malaria infection was significantly elevated in P. berghei infected mice compared to uninfected control mice (Fig. 1)
Cytokine dysregulation has been recognized as the major cause of several immunopathological events that occur during malaria infection [27]
Summary
The immune modulating potential of IL-35 in multiple human disorders has been reported. Associated molecular patterns (PAMP) akin to glycosylphosphatidylinositol (GPI), various parasite proteins and the pro-oxidant malarial pigment (haemozoin) trigger the robust release of pro-inflammatory cytokines tumour necrosis factor (TNF) and interleukin-1 (IL-1) by pattern recognition receptors [5, 7]. This pro-inflammatory cytokine profile (TNF and IL-1) sets in motion a cascade of events encompassing the recruitment of macrophages and inflammatory cells, nitric oxide (NO) production, alterations in vascular permeability, up regulation of adhesion molecules and microvascular accumulation of parasitized erythrocytes [7]. In general during acute malaria infection, the net effect of interactions between rapid pro-inflammatory Th1 type responses at the early stage(s) of infection generally mediated by IL-12, TNF, IL-6 and IFN-γ (necessary for parasite control) and robust timely anti-inflammatory Th-2 restricted responses mediated primarily by IL-10, IL-4 and TGF-β (vital for prevention of tissue damage) determine disease outcome [7, 9]
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