RESUMEN
BACKGROUND: Integrins, important extracellular matrix (ECM) receptor proteins, are affected by inflammation and can participate in the maintenance of many painful conditions. Although they are ubiquitous and changeable across all cell types, the roles of these cell adhesion molecules in pathological pain have not been fully explored. OBJECTIVE: We evaluated the effects of the subcutaneous injection of lebecetin, a C-type lectin isolated from Macrovipera lebetina snake venom, previously reported to inhibit α5ß1 and αv integrin activity, on different components of inflammation induced by the formalin administration in the hind paw of mice. METHODS: The formalin-induced nocifensive behavior, edema, and histopathological changes in the hind paw associated with cytokine, iNOS, and COX2 expression, nociceptive-specific neuron activity, and microglial activation analysis in the spinal cord were evaluated in mice receiving vehicle or lebecetin pretreatment. RESULTS: Lebecetin inhibited the nocifensive responses in the formalin test, related edema, and cell infiltration in the injected paw in a biphasic, hormetic-like, and dose-dependent way. According to that hormetic trend, a reduction in pro-inflammatory cytokines IL-6, IL-8, and TNF-alpha and upregulation of the anti-inflammatory cytokine IL-10 in the spinal cord were found with the lowest doses of lebecetin. Moreover, COX2 and iNOS expression in serum and spinal cord followed the same biphasic pattern of cytokines. Finally, nociceptive neurons sensitization and activated microglia were normalized in the dorsal horn of the spinal cord by lebecetin. CONCLUSION: These findings implicate specific roles of integrins in inflammation and tonic pain, as well as in the related central nervous system sequelae.
RESUMEN
The excessive production of inflammatory mediators results in an overactive immune response leading to the worsening of various human diseases. Thus, there is a still need to identify molecules able to regulate the inflammatory response. Lebecetin, a C-type lectin protein isolated from Macrovipera lebetina snake venom, was previously characterized as a platelet aggregation inhibitor and antitumor active biomolecule. In the present work, we investigated its effect on the production of some cytokines linked to inflammatory response and the underlying mechanisms in lipopolysaccharide (LPS)-induced THP1 macrophages. Interestingly, we found that lebecetin reduced the levels of the pro-inflammatory cytokines TNF-α, IL-6, and IL-8 while it partially increased LPS-induced secretion of the immunomodulatory cytokine IL-10. Furthermore, this modulatory effect was accompanied by decreased activation of ERK1/2, p38, AKT kinases and NF-κB along with reduced expression of αvß3 integrin. Thus, this study highlights the promising role of lebecetin as a natural biomolecule that could manage the inflammatory response involved in the development and progression of inflammatory diseases.
Asunto(s)
Citocinas/metabolismo , Venenos de Víboras/farmacología , Animales , Humanos , Interleucina-10/metabolismo , Lectinas Tipo C , Lipopolisacáridos , FN-kappa B/metabolismo , Venenos de Serpiente , ViperidaeRESUMEN
INTRODUCTION: Integrins are a family of multi-functional cell-adhesion molecules, heterodimeric receptors that connect extracellular matrix (ECM) to actin cytoskeleton in the cell cortex, thus regulating cellular adhesion, migration, proliferation, invasion, survival, and apoptosis. Consequently, integrins play a role in inflammation, angiogenesis and fibrosis. AREAS COVERED: This review examines individual anti-integrin agents in terms of their chemical nature, route of administration, and anti-integrin action. It also provides a summary of preclinical and clinical studies. Current clinical candidates include risuteganib, THR-687, and SF-0166, which have shown promise in treating diabetic macular edema (DME) and/or age-related macular degeneration (AMD) in early clinical studies. Preclinical candidates include SB-267268, AXT-107, JNJ-26076713, Cilengitide and Lebecetin, which exhibit a decrease in retinal permeability, angiogenesis and/or choroidal neovascularization (CNV). EXPERT OPINION: Anti-integrin therapies show potential in treating retinal diseases. Anti-integrin agents tackle the multi-factorial nature of diabetic retinopathy (DR) and AMD and show promise as injectable and topical agents in preclinical and early clinical studies. Integrin inhibition has potential to serve as primary therapy, adjunctive therapy to anti-vascular endothelial growth factor agents, or secondary therapy in refractory cases.