Substance P (SP) Induces Expression of Functional Corticotropin-Releasing Hormone Receptor-1 (CRHR-1) in Human Mast Cells

Abstract

Corticotropin-releasing hormone (CRH) is secreted under stress and regulates the hypothalamic-pituitary-adrenal (HPA) axis. However, CRH is also secreted outside the brain where it exerts pro-inflammatory effects through activation of mast cells, which are increasingly implicated in immunity and inflammation. Substance P (SP) is also involved in inflammatory diseases. Human LAD2 leukemic mast cells express only CRHR-1 mRNA weakly. Treatment of LAD2 cells with SP (0.5–2 µM) for 6 hr significantly increases CRHR-1 mRNA and protein expression. Addition of CRH (1 µM) to LAD2 cells “primed” with SP for 48 hr and then washed, induces synthesis and release of IL-8, tumor necrosis factor (TNF) and vascular endothelial growth factor (VEGF) 24 hr later. These effects are blocked by pretreatment with an NK-1 receptor antagonist. Treatment of LAD2 cells with CRH (1 µM) for 6 hr induces gene expression of NK-1 as compared to controls. However, repeated stimulation of mast cells with CRH (1 µM) leads to downregulation of CRHR-1 and upregulation in NK-1 gene expression. These results indicate that SP can stimulate mast cells and also increase expression of functional CRHR-1, while CRH induces NK-1 gene expression. These results may explain CRHR-1 and NK-1 expression in lesional skin of psoriatic patients.

Synthesis, F-18 radiolabeling, and microPET evaluation of 3-(2,4-dichlorophenyl)-N-alkyl-N-fluoroalkyl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7-amines as ligands of the corticotropin-releasing factor type-1 (CRF1) receptor

“…Both [ 18 F] 26 and [ 18 F] 27 show rapid uptake and then a steady washout from these regions but do not show the steady continuous uptake that was observed with [ 18 F] 28 , [ 18 F] 28- d 8 , and [ 18 F] 29 which supports the notion that some of the uptake of [ 18 F] 28 , [ 18 F] 28- d 8 , and [ 18 F] 29 in the sphenoid region, and possibly the skull, is due to binding to CRF 1 receptors expressed on mast cells in the bone marrow 43, 112, 116 and not solely the result of metabolically generated [ 18 F]fluoride. Furthermore, the lower binding affinity compound, [ 18 F] 26 , washes out faster from the skull and sphenoid region than the higher binding affinity compound, [ 18 F] 27 , which is in agreement with the idea that binding to the CRF 1 receptor expressed on bone marrow mast cells is being observed.…”

“…85 Thus, some of the observed sphenoid uptake of [ 18 F] 28 and [ 18 F] 28- d 8 may be the result of binding in bone marrow. Mast cells, which are derived from bone marrow 111, 112 and are also located intracranially, 113-115 have been shown to express CRF 1 receptors, 43, 112, 116-124 and this would help to explain the uptake of [ 18 F] 28 and [ 18 F] 28- d 8 (and [ 11 C] 6 , [ 11 C] 7 , and [ 11 C] 8 ) in the sphenoid region. Mast cells present in the skin also express CRF 1 receptors 125-127 which explains the radioactivity uptake observed in the skin in the coronal and sagittal images in Figures S2 and S3 (Supplementary Material).…”

“…114, 141 They are involved in the allergic response, including the allergic response to anesthesia, 142 and they can also be activated by non-allergic triggers, 143 including CRF. 113, 118, 121, 122, 125, 126 Mast cells express CRF 1 receptors 43, 112, 116, 118, 119 and also synthesize and secrete CRF, 117 and thus the two are closely linked. Activation of mast cells results in the release of histamine and other chemical messengers, 111 and histamine has been shown to increase levels of CRF in rats.…”

Chronic Stress Suppresses the Expression of Cutaneous Hypothalamic–Pituitary–Adrenocortical Axis Elements and Melanogenesis

“…Corticosterone-treated mice had decreased cutaneous expression levels of CRHR1 and CRHR2, whereas stressed mice showed no significant differences. Substance P can increase the expression of CRHR1 in mast cells in human skin [57]. There is increased Substance P protein expression in cutaneous peripheral nerve fibers in chronically stressed mice [58].…”

Stress-Induced Mast Cell Activation in Glabrous and Hairy Skin

“…Moreover, substances released by mast cells, such as histamine, serotonin, and proinflammatory cytokines, may have a modulatory action on nerve fibers function and neuropeptides effects [50, 72, 73]. …”