Differential effects of curcumin on renal and systemic inflammation in a mouse model of systemic lupus erythematosus
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Purpose: The afferent vagus nerve, through its connection to the hypothalamic pituitary adrenal (HPA) axis, may help regulate inflammation by relaying inflammatory stimuli to prompt release of the anti-inflammatory hormone cortisol. Afferent vagal sensitivity may be diminished in chronic inflammatory diseases, such as systemic lupus erythematosus (SLE). SLE primarily affects reproductive age women, who commonly present with inflammatory kidney disease, diminished vagal tone, dysregulated HPA function, and inadequate basal cortisol. There is evidence that curcumin, the active compound of the spice turmeric, activates vagal afferent neurons, which may lead to increased HPA axis function and heightened cortisol release. We hypothesized that chronic curcumin administration (50mg/kg in sesame oil as vehicle; 4 weeks, daily; i.p.) would protect against chronic inflammation in the NZBWF1 mouse model of SLE by ameliorating HPA axis dysfunction. Methods: At 30 weeks of age, female mice were designated into four groups (n = 4-5/group): SLE-CURC, SLE-VEH, CTL-CURC, and CTL-VEH. We measured splenic cytokines as endogenously released cortisol from the HPA aixis modulates activity of this immune organ. Results: Splenic TNF-α and IL-1β expression (normalized to total protein) were increased in SLE mice compared to controls (2.57 x 107 ± 4.41 x 106 vs. 1.56 x 107 ± 1.99 x 106; p = 0.006 and 2.76 x 105 ± 9.86 x 104 vs. 3.35 x 104 ± 2.49 x 104; p = 0.020). Curcumin accentuated splenic TNF (4.85 x 107 ± 7.06 x 106; p = 0.016), while reducing splenic IL-1β in SLE mice (1.36 x 105 ± 1.74 x 104; p = 0.092). Preliminary in vitro splenocyte data support curcumin as being pro-inflammatory in SLE. Splenocytes isolated from curcumin- and vehicle-treated SLE mice released increased TNF-α when stimulated with LPS (100 ng) or norepinephrine (50 nM), (2.76 x 105 vs. 6.88 x 104 and 4.69 x 105 vs. 1.42 x 105, respectively; n = 1/group). In order to determine curcumin’s effects on kidney inflammation, we measured renal cytokine expression. SLE mice had elevated renal cortical IL-6 and TGF-β1 compared to control mice (1.27 x 105 ± 6.16 x 104 vs. 7.49 x 104 ± 1.50 x 104; p = 0.130 and 1.90 x 105 ± 7.17 x 104 vs. 7.67 x 103 ± 2.58 x 103; p = 0.006). Curcumin increased renal cortical expression of both IL-6 and TGF-β1 in SLE mice (3.37 x 105 ± 1.44 x 104 vs. 1.28 x 105 ± 6.16 x 104; p = 0.128 and 3.536 x 105 ± 1.16 x 105 vs. 1.90 x 105 ± 7.17 x 104; p = 0.152). Conclusions: Taken together these data indicate that curcumin mostly yields pro-inflammatory effects in the setting of SLE, although its anti-inflammatory suppression of splenic IL-1β suggests a more complex interaction with the immune system. Additional studies are needed to investigate renal and cardiovascular outcomes. Further inquiry into vagal control of inflammation and the use of naturally derived compounds as an adjunct treatment of chronic inflammatory processes is warranted.