Interleukin-1 receptor antagonist decreases cerebrospinal fluid nitric oxide levels and increases vasopressin secretion in the late phase of sepsis in rats

Abstract

The aim of this study was to analyze the effect of IL-1ra (an Interleukin-1 receptor antagonist) on sepsis-induced alterations in vasopressin (AVP) and nitric oxide (NO) levels. In addition, IL-1ra effect on the hypothalamic nitric oxide synthase (NOS) activities and survival rate was also analyzed. After Wistar rats were intracerebroventricular injected with IL-1ra (9 pmol) or vehicle (PBS 0.01 M), sepsis was induced by cecal-ligation and puncture (CLP). Blood, CSF, and hypothalamic samples were collected from different groups of rats (n = 8/group) after 4, 6, and 24 h. AVP and NO levels were greatly increased in CLP. Both total NOS and inducible NOS (iNOS) activities were also greatly increased in CLP rats. These changes in AVP, NO, and NOS were not observed in sham-operated control rats. IL-1ra administration did not alter plasma AVP levels after 4 and 6 h as compared to vehicle in CLP animals but after 24 h were significantly (P < 0.01) higher in IL-1ra-treated animals. IL-1ra administration significantly (P < 0.01) decreased NO concentration in CSF but not in plasma. Both total NOS and iNOS activities were also significantly decreased by IL-1ra at 24 h in CLP animals. Moreover, the 24 h survival rate of IL-1ra-treated rats increased by 38 % in comparison to vehicle administered animals. The central administration of IL-1ra increased AVP secretion in the late phase of sepsis which was beneficial for survival. We believe that one of the mechanisms for this effect of IL-1ra is through reduction of NO concentration in CSF and hence lower hypothalamic iNOS activities in the septic rats.

Interleukin-1 Receptor Antagonist Decreases Hypothalamic Oxidative Stress During Experimental Sepsis

“…It is marked by widespread alterations in major biochemical regulatory pathways. Several studies have reported alterations in IL-1, NO, and AVP signaling pathways during sepsis [1,6,[8][9][10][19][20][21][22][23][24][25]. In the current study, in agreement with results of previous reports, we also noted that the hypothalamic gene and protein expressions of IL-1 and iNOS are significantly increased during sepsis.…”

“…In a recent study [1], we observed that blocking the IL-1-IL-1r signaling pathway in the central nervous system by i.c.v. injection of IL-1ra, an antagonist of the IL-1 receptor, greatly reduced iNOS activity in the hypothalamus and diminished the NO concentration in CSF.…”

“…AVP secretion during sepsis can be separated into two distinct phases [1][2][3]. In the initial phase, AVP secretion is increased in response to the drop in blood pressure, representing a normal endocrine response pattern, but in the late phase, its secretion is inappropriately low regardless of progressive, life-threatening hypotension [1][2][3][4][5][6][7].…”

“…The currently available data suggest the involvement of a large array of molecular factors in inducing alterations in AVP secretion during sepsis [8]. Among these, IL-1, NO, cleaved caspase 3, and HIF-1 have been pinpointed as important factors for the impairment of AVP secretion during the late phase of severe sepsis [1,6,[8][9][10].…”

Vitamin A affects the expression of antioxidant genes in bovine mammary epithelial cells with oxidative stress induced by diethylene triamine-nitric oxide

“…Balato et al (2013) found that the pro-inflammatory factor TNF-α enhanced the gene expression of IL-1 in human skin tissue in vivo and it was inhibited by RA. Wahab et al (2015) found that the interleukin-1 receptor antagonist could also decrease the NO concentration in cerebrospinal fluid and lower iNOS activities in the septic rat. Dheen et al (2005) and Hong et al (2014) indicated that RA inhibited the production of TNF-α and decreased the gene expression of iNOS in murine RAW264.7 cells and in activated rat microglia induced by LPS to reduce NO production.…”