Inflammatory cytokines in vitro production are associated with Ala16Val superoxide dismutase gene polymorphism of peripheral blood mononuclear cells

Abstract

Obesity is considered a chronic low-grade inflammatory state associated with a chronic oxidative stress caused by superoxide production (O(2)(-)). The superoxide dismutase manganese dependent (SOD2) catalyzes O(2)(-) in H(2)O(2) into mitochondria and is encoded by a single gene that presents a common polymorphism that results in the replacement of alanine (A) with a valine (V) in the 16 codon. This polymorphism has been implicated in a decreased efficiency of SOD2 transport into targeted mitochondria in V allele carriers. Previous studies described an association between VV genotype and metabolic diseases, including obesity and diabetes. However, the causal mechanisms to explain this association need to be more elucidated. We postulated that the polymorphism could influence the inflammatory response. To test our hypothesis, we evaluated the in vitro cytokines production by human peripheral blood mononuclear cells (PBMCs) carrier's different Ala16Val-SOD2 genotypes (IL-1, IL-6, IL-10, TNF-α, IFN-γ). Additionally, we evaluated if the culture medium glucose, enriched insulin, could influence the cytokine production. Higher levels of proinflammatory cytokines were observed in VV-PBMCs when compared to AA-PBMCs. However, the culture medium glucose and enriched insulin did not affect cytokine production. The results suggest that Ala16Val-SOD2 gene polymorphism could trigger the PBMCs proinflammatory cytokines level. However, discerning if a similar mechanism occurs in fat cells is an open question.

Impact of obesity and Ala16Val MnSOD polymorphism interaction on lipid, inflammatory and oxidative blood biomarkers

“…These results suggest that superoxide imbalance associated to V allele (VV or AV) could to be related to inflammatory plasmatic biomarkers. The result corroborates the in vitro study performed by Montano et al [22] that evaluated cytokines production by human peripheral blood mononuclear cells (PBMCs) carrier's different Ala16Val-SOD2 genotypes and found higher levels of proinflammatory cytokines in VV-PBMCs when compared to AA-PBMCs.…”

“…Previously, Montano et al [14] described positive association between VV genotype and obesity and other studies also described association with hypercholes-terolemia [15], diabetes or diabetic cardiovascular diseases [16,17] diabetic nephropathy [18] and diabetic retinopathy [19], elevate plasmatic oxided-LDL levels mainly in diabetic patients [20], elevate also lipid peroxidation, protein carbonylation [10,21] and proinflammatory-cytokines (IL-1β, IL-6, TNFα and Igɣ) [22].…”

Association between Polymorphisms in Antioxidant Genes and Inflammatory Bowel Disease

“…gastric, lung, prostate, bladder and breast, to diabetes type I, nephropathy, chronic kidney disease, and to chemotherapy responses. The Ala16Ala genotype is generally associated with a protective effect, yet important differences are described in the literature, which indicates a complex role for the presence of risk allele C. Also, it has been suggested that SOD2 16Val variant is associated with an increased production of pro-inflammatory cytokines [43], and that its expression can be modulated through NF-kB binding to the promoter region of the gene [44]. …”

Mn-SOD 47 CC genotype in combination with high tea consumption may prevent complications in Tunisian type-2 diabetes

“…It has been reported that the altered Mn-SOD variant increases the risk of oxidative stress associated with various pathologies, including diabetic microvascular disease (Chistyakov et al, 2001;Lee and Choi, 2006;Eras-Erdogan et al, 2009;Chen et al, 2012). Mn-SOD may be the most important member of the SOD family; therefore, people presenting Mn-SOD gene mutations are subjected to lower Mn-SOD efficiency and might be more prone to complications (Kariž et al, 2012;Montano et al, 2012). In our study, we found that the Mn-SOD CC genotype may protect against the development of complications in Tunisian T2D.…”

“…A meta-analysis showed a significant association of the T47C C allele of Mn-SOD with reduced risk of diabetic microvascular complications including diabetic nephropathy, diabetic retinopathy, and diabetic polyneuropathy in dominant, recessive, and codominant models (Tian et al, 2011). The SODs are a class of enzymes involved in the detoxification of superoxide into hydrogen peroxide (Montano et al, 2012). Three major isoforms of SOD have been identified according to their tissue location and transition metals.…”