C-Reactive Protein and Interleukin-6 Are Decreased in Transgenic Sickle Cell Mice Fed a High Protein Diet

Abstract

Sickle cell disease is associated with hypermetabolism and a consequent shortage of substrates for normal growth and healthy immune response. The protein:energy ratio is a major determinant of dietary adequacy; the requirement for optimal growth of control mice is 20% of energy from dietary protein. This study investigated the efficacy of increased dietary protein for improving weight gain and reducing inflammation in the Berkeley sickle cell mouse model (S). The study examined the effect of diet on weight gain and circulating levels of 2 inflammatory proteins, C-reactive protein (CRP), and cytokine interleukin-6 (IL-6). Male C57BL/6 (C) control (n = 8) and S mice (n = 8) were randomized at weaning to 40 d of isoenergetic diets containing 20% (normal) and 35% (high) of energy from protein (C20, C35, S20, S35), replacing dextrin. Rate of weight gain was calculated and plasma CRP and IL-6 concentrations determined by ELISA. Liver mRNA expression of these proteins was measured by real-time PCR and L-arginase by colorimetric assay. S35 mice tended to gain weight more rapidly than S20 mice (P = 0.06) and more rapidly than C35 mice (P < 0.01). Circulating CRP and IL-6 levels were also lower in S35 mice than in S20 mice (P < 0.05), as was liver CRP mRNA expression (P < 0.01). These results demonstrate that introducing a high protein diet at weaning attenuates the steady-state inflammation in this S mouse model. Dietary L-arginine availability was investigated as a possible mechanism for increased nitric oxide production and consequent reduced inflammation.

A randomized, placebo-controlled trial of arginine therapy for the treatment of children with sickle cell disease hospitalized with vaso-occlusive pain episodes

“…[25][26][27] Arginine also increases erythrocyte glutathione levels in both mice 25 and humans, 28 and may down-regulate inflammatory pathways. 29 In addition, arginine is a key substrate in creatine synthesis, an important metabolic pathway not yet sufficiently studied in SCD that may be affected by an arginine-deficient state. Although the role of NO in SCD has become controversial, 30,31 these studies demonstrate that the mechanistic impact of arginine goes beyond NO.…”

“…35 Previous studies have shown that low-dose arginine is unlikely to affect NO synthesis, 35 an observation confirmed in SCD by the CSCC study. 34 Since the capacity of arginine to increase NO x production in SCD and VOE is dose-dependent, 20 higher concentrations of plasma arginine are likely needed 29 to overcome multi-factorial effects including the impact of arginase and asymmetric dimethylarginine (ADMA) on global arginine bioavailability.…”

TNF-α, IFN-γ, IL-10, and IL-4 levels were elevated in a murine model of human sickle cell anemia maintained on a high protein/calorie diet

“…These are iso-caloric diets providing either 20% or 35% of calories as protein by adjusting the dextrin concentration. 30 Hence, eight C57BL/6 or control mice were randomized to the 20% protein diet and were labeled C20 and 8–35% protein (C35). Similarly, SCA mice were randomized to either the 20% (S20, n = 8) or 35% protein diet (S35, n = 8).…”

“…30,31 Furthermore, malnourished mice have been shown to have decreased expression of Toll-like receptor 4 (TLR-4), which along with TNF-α mediates the acute inflammatory response to infection. In addition, malnourished mice show decreased expression of TNF-α compared with controls.…”

C-Reactive Protein Polymorphism and Serum Levels as an Independent Risk Factor in Sickle Cell Disease

“…One study demonstrated an increase in CRP in the prodromal phase of vaso-occlusive crisis (n = 10) [123]. Recently, researchers have looked for an association between CRP levels and hypermetabolism, as it affects growth and development in SCD patients [124]. A gap in the literature remains on the relationship of CRP to secondary complications and specifically end-organ dysfunction that effect the adult SCD population.…”