Toftegaard C L, Knigge U, Kjaer A, Watanabe T, Friis-Hansen L, Warberg J
Department of Medical Physiology, Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Neuroimmunomodulation. 2002;10(6):344-50. doi: 10.1159/000071475.
Circulating cytokines such as interleukin-1 (IL-1), and tumor necrosis factor-alpha as well as lipopolysaccharide (LPS) are potent ACTH secretagogues, acting via stimulation of corticotropin-releasing hormone (CRH) and vasopressinergic neurons in the paraventricular nucleus of the hypothalamus (PVN). Histamine (HA) has been shown to stimulate ACTH secretion in rats, an effect in part mediated by CRH and arginine vasopressin (AVP). We have previously shown that inhibition of neuronal HA synthesis or central blockade of H(1) receptors (H(1)R) decreased the ACTH response to LPS in male rats. To further elucidate the role of neuronal HA in cytokine-induced activation of the HPA axis, we compared the effect of H(1)R knockout on IL-1beta-induced ACTH secretion in adult male mice.
In H(1)R knockout mice, ACTH secretion increased from basal levels of 261 to 492 pmol/l in response to IL-1beta whereas the cytokine-induced ACTH secretion increased from 140 to 406 pmol/l in wild-type mice. Plasma corticosterone (CORT) rose from basal levels of 99 to 831 nmol/l in knockout mice upon IL-1beta stimulation, whereas in wild-type mice CORT levels rose from 112 to 841 nmol/l. There was no significant difference in IL-1beta-stimulated plasma ACTH or CORT levels between wild-type and knockout mice. Furthermore, there was no significant difference in basal or IL-1beta-stimulated hypothalamic levels of histamine and tele-methyl-histamine between wild-type and knockout mice. HDC gene expression was significantly lower in knockout mice than in wild-type mice both under basal and IL-1beta-stimulated conditions, while there were no significant differences in CRH gene expression in the PVN in knockout mice under basal and IL-1beta-stimulated conditions. Increased basal expression of AVP in the PVN of knockout mice was observed in this study compared to wild-type mice.
We conclude that the lack of the gene for histamine H(1)R does not seem to be crucial for the ACTH and CORT response to IL-1beta, either due to possible functional compensation in the H(1)R knockout mouse or due to activation of pathways other than the neuronal histaminergic system.
循环细胞因子如白细胞介素-1（IL-1）、肿瘤坏死因子-α以及脂多糖（LPS）都是强效促肾上腺皮质激素释放因子，它们通过刺激下丘脑室旁核（PVN）中的促肾上腺皮质激素释放激素（CRH）和血管加压素能神经元发挥作用。组胺（HA）已被证明可刺激大鼠促肾上腺皮质激素的分泌，这一作用部分由CRH和精氨酸血管加压素（AVP）介导。我们之前的研究表明，抑制神经元HA合成或中枢阻断H（1）受体（H（1）R）可降低雄性大鼠对LPS的促肾上腺皮质激素反应。为了进一步阐明神经元HA在细胞因子诱导的下丘脑-垂体-肾上腺（HPA）轴激活中的作用，我们比较了H（1）R基因敲除对成年雄性小鼠IL-1β诱导的促肾上腺皮质激素分泌的影响。
在H（1）R基因敲除小鼠中，IL-1β刺激后促肾上腺皮质激素分泌从基础水平的261pmol/l增加到492pmol/l，而在野生型小鼠中，细胞因子诱导的促肾上腺皮质激素分泌从140pmol/l增加到406pmol/l。IL-1β刺激后，基因敲除小鼠血浆皮质酮（CORT）从基础水平的99nmol/l升至831nmol/l，而野生型小鼠CORT水平从112nmol/l升至841nmol/l。野生型和基因敲除小鼠在IL-1β刺激后的血浆促肾上腺皮质激素或CORT水平上没有显著差异。此外，野生型和基因敲除小鼠在基础状态或IL-1β刺激下，下丘脑组胺和甲基组胺水平也没有显著差异。在基础状态和IL-1β刺激条件下，基因敲除小鼠中组胺脱羧酶（HDC）基因表达均显著低于野生型小鼠，而在基础状态和IL-1β刺激条件下，基因敲除小鼠PVN中CRH基因表达没有显著差异。与野生型小鼠相比，本研究观察到基因敲除小鼠PVN中AVP基础表达增加。
我们得出结论，组胺H（1）R基因缺失似乎对促肾上腺皮质激素和CORT对IL-1β的反应并非至关重要，这可能是由于H（1）R基因敲除小鼠中存在功能补偿，或者是由于神经元组胺能系统以外的途径被激活。
