Different Role of cAMP Pathway on the Human Mast Cells HMC‐1⁵⁶⁰ and HMC‐1^560,816 Activation

Abstract

HMC-1 are inflammatory cells that release vasoactive substances such as histamine. These cells have the c-kit receptor permanently activated in the membrane due to mutations in the proto-oncogene c-kit: Val-560 → Gly and Asp-816 → Val. Thus, there are two known cellular lines: HMC-1(560) and HMC-1(560,816) . These mutations are involved in a disease called mastocitosys. In the present paper both lines were used to study the influence of cAMP/PKA/PDEs pathway on the histamine release and Ca(2+) signaling since this pathway is often involved in these process. For this, the cells were preincubated with cAMP/PKA/PDEs modulators such as dibutyryl cAMP (dbcAMP), forskolin, H89, rolipram, IBMX, or imidazole and then stimulated with ionomycin. When cells were stimulated with agents that increase cAMP levels, the histamine release was not modified in HMC-1(560) but decreased in HMC-1(560,816) cells. The same happened when PKA was blocked. Furthermore, PDEs role on histamine release was independent of cAMP in HMC-1(560) cells and possibly also in HMC-1(560,816) cells. By contrast, the modulation of PKA and PDEs together changed the response in both cellular lines, therefore a relationship between them was suggested. All these modulatory effects on histamine release are Ca(2+) -independent. On the other hand, the effect of c-kit modulation on the cAMP/PKA/PDEs pathway was also checked. This receptor was blocked with STI571 (imatinib) and BMS-354825 (dasatinib), but only the last one caused a decrease in the cellular response to ionomycin. This article demonstrates for the first time than the cAMP/PKA/PDEs pathway is involved in the activation of HMC-1(560) and HMC-1(560,816) cells.

Prophylactic or therapeutic administration of Holarrhena floribunda hydro ethanol extract suppresses complete Freund’s adjuvant-induced arthritis in Sprague-Dawley rats

“…cAMP and its effector, PKA, are implicated in the resolution of acute inflammation [ 87 ] and are generally regarded as anti-inflammatory [ 88 – 90 ]. Further, cAMP has been shown to inhibit histamine release from human mast cells [ 91 ] and is reported to be key in several endogenous processes involved in preventing acute inflammation from progressing to deleterious chronic inflammation [ 92 ]. HFE reduced WBC and ESR (Table 3 ), both of which are markers of inflammation status [ 55 – 61 ], compared with the CFA arthritic control.…”

Prophylactic or therapeutic administration of Holarrhena floribunda hydro ethanol extract suppresses Complete Freund’s Adjuvant-induced arthritis in Sprague-Dawley rats    

“…cAMP and its effector, PKA, are implicated in the resolution of acute in ammation (Lima et al, 2017) and are generally regarded as anti-in ammatory (Campo et al, 2012;Oldenburger et al, 2012;Wang et al, 2020). Interestingly, cAMP has been shown to inhibit histamine release from human mast cells (Barreiro-Costa et al, 2014) and is reported to be key in several endogenous processes involved in preventing acute in ammation from progressing to deleterious chronic in ammation (Moore & Willoughby, 1995). Indeed, HFE reduced WBC and ESR (Table 3), both of which may be used as markers of in ammation status (Carr et al, n.d.;Farhangi et al, 2013;Harrison, 2015;Ingelsson et al, 2005;Kounis et al, 2014;Ong et al, 2015;Watson et al, 2012).…”