Interleukin‐10 Suppresses Sympatho‐Excitatory Responses to Central LPS in Rats

Abstract

The role of the anti-inflammatory cytokine interleukin (IL)-10 in counteracting endotoxin (LPS)-induced acute phase sympatho-excitatory responses has not been studied. In male rats, adenoviral vectors encoding human IL-10 (ADIL10, 30 μL; 3x1010 plaque-forming units) or β-galactosidase (βGal) were injected into the lateral ventricle. One week later, under anesthesia, renal sympathetic nerve activity (RSNA, %Δ), mean arterial pressure (MAP, ΔmmHg) and heart rate (HR, Δbpm) were recorded during intracerebroventricular (ICV) of LPS (4 μg). Cerebrospinal fluid (CSF) and hypothalamic tissue were collected 4 hr after LPS injection. Abundant gene expression of ADIL10 mRNA was detected by RT-PCR in the hypothalamus after ADIL10 (n=4) but not βGal (n=4). After ADIL10, LPS elicited significantly (∗p<0.05, vs βGal, n=5) smaller increases in RSNA (26.6 ± 7.8∗ vs 50.2 ± 8.4), HR (33.6 ± 12.2∗ vs 91.6 ± 10.7), MAP (4.4 ± 2.4∗ vs 15.7 ± 3.6), hypothalamic cyclooxygenase-2 (COX-2) mRNA (0.09 ± 0.01∗ vs 0.17 ± 0.02; real-time PCR, normalized to GAPDH mRNA) and CSF prostaglandin E2 (PGE2) (466 ± 78∗ vs 1078 ±153 pg/ml; ELISA). Acute ICV injection of IL-10 (0.5 μg, n=5) 5–10 min prior to ICV LPS resulted in similar significant reductions in RSNA, HR, MAP, hypothalamic COX-2 mRNA and CSF PGE2, sampled 4 hr later. ICV NS398 (2 μg, n=5), a specific COX-2 inhibitor, also blocked LPS-induced sympatho-excitatory responses. We conclude that IL-10 has a potent inhibitory influence on central neural mechanisms regulating sympathetic drive, and may have therapeutic potential in the treatment of cardiovascular diseases with an inflammatory component. Supported by NIH HL-073986.