RESUMO
Synovium hyperplasia characterizes joint diseases, such as rheumatoid arthritis (RA). The cytotoxic effect of low-dose Cadmium (Cd) was tested in vitro and ex vivo on synoviocytes, the mesenchymal key effector cells of inflammation and proliferation in arthritis. The anti-inflammatory and anti-proliferative effects of Cd were tested in vivo by intra-articular injection in the adjuvant induced arthritis rat joints, where the clinical scores and the consequences of arthritis were evaluated. Cell death through apoptosis was highly induced by Cd in inflammatory synoviocytes (80% reduction of cell viability, p < 0.01). TNF plus IL-17 cytokine combination induced a two-fold increase of Cd cell content by enhancing the ZIP-8 importer and the MT-1 homeostasis regulator expression. Addition of Cd reduced IL-6 production in TNF plus IL-17-activated synoviocytes (up to 83%, p < 0.05) and in ex-vivo synovium biopsies (up to 94%, p < 0.01). Cd-injection in rat joints improved arthritis, reducing clinical scores (arthritic score reduced from 4 to 2, p < 0.01), inflammatory cell recruitment (up to 50%, p < 0.01) and protecting from bone/cartilage destruction. This proof of concept study is supported by the limited Cd spread in body reservoirs, with low-dose Cd providing a safe risk/benefit ratio, without toxic effects on other cell types and organs.
Assuntos
Artrite/etiologia , Artrite/metabolismo , Cádmio/administração & dosagem , Articulações/metabolismo , Substâncias Protetoras/administração & dosagem , Animais , Artrite/tratamento farmacológico , Artrite/patologia , Artrite Experimental , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/etiologia , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Biópsia , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Sobrevivência Celular/genética , Sobrevivência Celular/imunologia , Modelos Animais de Doenças , Feminino , Expressão Gênica , Humanos , Interleucina-6/biossíntese , Articulações/efeitos dos fármacos , Articulações/patologia , Camundongos , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Microtomografia por Raio-XRESUMO
Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis.