The effect of Anti-TNF-α Antibody on Leishmania major Infection as to Hyperalgesia and the Cytokine Interplay

Abstract

Cutaneous Leishmaniasis is a disease caused by the flagellated promastigote form of the Leishmania major parasite. The infection of the susceptible BALB/c mice with a high dose of this intracellular parasitic protozoan induces a sustained hyperalgesic response accompanied by up-regulation of the pro-inflammatory cytokines Interleukin-1β (IL-1β) and Interleukin-6 (IL-6). Interleukin-13 (IL-13) has been shown to reduce this hyperalgesia when IL-6 levels are increased and to reduce IL-1β levels during and after the treatment period. These observations imply that cytokine signaling cascades lead to the production of sympathetic amines via TNF-α and Keratinocyte Derived Chemokine (IL-8-like analogue) but not via prostaglandins. However, the role of TNF-α in L. major- induced hyperalgesia and its mechanism of action have not been elucidated. This study investigates the effects of anti TNF-α monoclonal antibody (Infliximab) on L. major-induced inflammation and hyperalgesia in mice and examines the levels of several inflammation-related cytokines. High doses of L. major parasites were injected in L. major susceptible BALB/c mice in the presence of Anti-TNF-α . The Hot Plate and Tail Flick tests were used to examine hyperalgesia and results showed that Anti-TNF-α significantly reduces L. major-induced hyperalgesia in a dose-dependent manner. The effects of anti-TNF-α injections on the cytokine levels were assessed using ELISA kits. Compared to control mice, TNF-α neutralization up-regulated "anti-inflammatory cytokines" such as IL-10 and downregulated "pro-inflammatory cytokines" such as IL-1β and IFN-γ. In addition, novel roles of IL-17 and KC in limiting leishmaniasis progression and hyperalgesia were established. Finally, the course of the infection was assessed via parasite burden and regression of parasite growth was observed in Anti-TNF-α antibody treated mice. Taken together, L. major-induced hyperalgesia was shown to be mediated by TNF-α which in turn may have a potential role in enhancing leishmaniasis progression in susceptible hosts.