Inflammatory vulnerability associated with the rh5-HTTLPR genotype in juvenile rhesus monkeys

Abstract

Individual variation in serotonergic function is associated with reactivity, risk for affective disorders, as well as an altered response to disease. Our study used a nonhuman primate model to further investigate whether a functional polymorphism in the promoter region for the serotonin transporter gene helps to explain differences in proinflammatory responses. Homology between the human and rhesus monkey polymorphisms provided the opportunity to determine how this genetic variation influences the relationship between a psychosocial stressor and immune responsiveness. Leukocyte numbers in blood and interleukin-6 (IL-6) responses are sensitive to stressful challenges and are indicative of immune status. The neutrophil-to-lymphocyte ratio and cellular IL-6 responses to in vitro lipopolysaccharide stimulation were assessed in 27 juvenile male rhesus monkeys while housed in stable social groups (NLL = 16, NS = 11) and also in 18 animals after relocation to novel housing (NLL = 13, NS = 5). Short allele monkeys had significantly higher neutrophil-to-lymphocyte ratios than homozygous Long allele carriers at baseline [t(25) = 2.18, P = 0.02], indicative of an aroused state even in the absence of disturbance. In addition, following the housing manipulation, IL-6 responses were more inhibited in short allele carriers (F1,16 = 8.59, P = 0.01). The findings confirm that the serotonin transporter gene-linked polymorphism is a distinctive marker of reactivity and inflammatory bias, perhaps in a more consistent manner in monkeys than found in many human studies.

Figure 1. Neutrophil-to-Lymphocyte Ratios and Interleukin-6 Responses

Mean values (+/− SE) values displayed for LL and S-carrier monkeys at Baseline (N_LL=16, N_S=11) and after Relocation Stress (N_LL=13, N_S=5). Relocation markedly affected the neutrophil-to-lymphocyte ratio and IL-6 levels in the LPS stimulated whole blood cultures. S-carriers had significantly higher neutrophil-to-lymphocyte ratios in the undisturbed condition and underwent greater stress-induced inhibition of IL-6 responses.