Chronic stress induces persistent low-grade inflammation

Abstract

Introduction: This study sought to determine if the systemic cytokine profile of rodents subjected to chronic restraint stress leads to persistent low-grade inflammation.

Methods: Male Sprague-Dawley rats were subjected to restraint stress for a total of seven or fourteen days. Urine norepinephrine (NE), plasma interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), C-reactive protein (CRP) were assessed with ELISA. Liver expression of IL-6 and TNF-α were assessed with real time PCR.

Results: Chronic stress at 7 and 14 days sequentially increased plasma acute phase reactants (NE, IL-6, TNF-α, and CRP), liver IL-6 expression, hematopoietic progenitor cell mobilization, and decreased erythroid progenitor colony growth. Weight gain was reduced by chronic stress compared to each models' naïve counterpart.

Conclusions: Combining this model with trauma and sepsis models will allow evaluation of the contribution of persistent inflammation in disease progression and outcomes.

Keywords: C-reactive protein; IL-6; Inflammation; Norepinephrine; Stress.

Fig. 1.

Chronic stress increased urine epinephrine. Seven days of restraint stress significantly increased urine norepinephrine, while it decreased from 7 to 14 days of stress. *p < 0.05 vs. naïve; **p < 0.05 CS 7 Day vs. CS 14 day.

Fig. 2.

A-D. Chronic stress increased plasma acute phase reactants. 2A. Plasma IL-6 increased significantly from naïve to 7 days of restraint stress, then again from 7 to 14 days of stress. 2B. Fourteen days of restraint stress significantly increased plasma TNF-α. 2C. Plasma CRP increased significantly from naïve to 7 days of restraint stress, then again from 7 to 14 days of stress. 2D. Plasma SDF-1 was not significantly affected by restraint stress. *p < 0.05 vs. naïve; **p < 0.05 CS 7 Day vs. CS 14 day.

Fig. 3.

A-B. Chronic stress increased expression of liver IL-6 and TNF-α. 3A. Fourteen days of restraint stress significantly increased liver expression of IL-6 compared to naïve and 7 days of stress. 3B. Seven days of restraint stress significantly increased spleen expression of TNF-α. *p < 0.05 vs. naïve; **p < 0.05 CS 7 Day vs. CS 14 day.

Fig. 4.

A-B. Chronic stress suppressed bone marrow erythroid progenitor colony growth. 4A. BFU-E was significantly suppressed after seven days of restraint stress, then further suppressed after 14 days of stress. 4B. CFU-E was significantly suppressed after seven days of restraint stress, then further suppressed after 14 days of stress. *p < 0.05 vs. naïve; **p < 0.05 CS 7 Day vs. CS 14 day.

Fig. 5.

Chronic stress increased HPC mobilization. HPC mobilization to the peripheral blood was significantly increased after 7 days of restraint stress, then further increased after 14 days of stress. HPC: hematopoietic progenitor cell; *p < 0.05 vs. naïve; **p < 0.05 CS 7 Day vs. CS 14 day.