Participation of mitogen‐activated protein kinase in thapsigargin‐ and TPA‐induced histamine production in murine macrophage RAW 264.7 cells

Abstract

1 Stimulation of the murine macrophage cell line RAW 264.7 with thapsigargin, an endomembrane Ca 2+ -ATPase inhibitor, induced histamine production in a time-and concentration-dependent manner. 2 The protein kinase C activator, 12-O-tetradecanoylphorbol 13-acetate (TPA), also enhanced histamine production. 3 a-Fluoromethylhistidine, a suicide substrate of L-histidine decarboxylase (HDC), suppressed the thapsigargin (30 nM)-and TPA (30 nM)-induced histamine production. 4 Both thapsigargin (30 nM) and TPA (30 nM) induced phosphorylation of p44/p42 MAP kinase and p38 MAP kinase. 5 PD98059, a speci®c inhibitor of MEK-1 which phosphorylates p44/p42 MAP kinase, strongly suppressed both the thapsigargin (30 nM)-and TPA (30 nM)-induced histamine production, whereas SB203580, a speci®c inhibitor of p38 MAP kinase, inhibited them only partially. 6 The other MEK-1 inhibitor, U-0126, also inhibited both the thapsigargin-and TPA-induced histamine production in a concentration-dependent manner. 7 Thapsigargin (30 nM) and TPA (30 nM) increased the levels of HDC mRNA at 4 h, but PD98059 suppressed both the thapsigargin-and TPA-induced increases in the HDC mRNA level. 8 These ®ndings indicate that thapsigargin and TPA induce histamine production in RAW 264.7 cells by increasing the level of HDC mRNA, and that both the thapsigargin-and TPA-induced histamine production are regulated largely by p44/p42 MAP kinase and partially by p38 MAP kinase.

Involvement of MAP kinases in lipopolysaccharide-induced histamine production in RAW 264 cells

“…Consistent with our previous findings that thapsigargininduced histamine production was inhibited almost completely by U0126 and partially by SB203580 (Shiraishi et al, 2000), the LPS-induced production of histamine also was suppressed by U0126 (Fig. 3b) and partially inhibited by SB203580 (Fig.…”

“…These inhibitory actions of U0126 were correlated with the inhibition of the LPS-induced phosphorylation of p44/42 MAP kinase (Fig. 3a), indicating that p44/42 MAP kinase plays critical roles in the LPS-induced as well as the thapsigargin-induced expression of HDC (Shiraishi et al, 2000). The involvement of p44/42 MAP kinase in the production of histamine was also indicated in other types of cells.…”

“…However, little has been reported on the molecular mechanism behind the LPS-induced increase in HDC activity in macrophages. We have reported that thapsigargin, a Ca 2+ -ATPase inhibitor, induces the expression of HDC and production of histamine in a murine macrophagelike cell line, RAW 264, and the thapsigargin-induced production of histamine is inhibited almost completely by the MAP kinase-Erk kinase (MEK) 1 inhibitors U0126 and PD98059 and partially by the p38 MAP kinase inhibitor SB203580 (Shiraishi et al, 2000). However, the involvement of c-Jun N-terminal kinase (JNK) in the production of histamine has remained to be clarified.…”

Topical Surfactant-Induced Pruritus: Involvement of Histamine Released from Epidermal Keratinocytes

“…These results, taken together, suggest that the histamine contained in the mast cells is not a causal mediator of topical sodium laurate-induced delayed scratching. Macrophages have been shown to have HDC activity and contain histamine in vitro (Kawaguchi-Nagata et al, 1988;Shiraishi et al, 2000). However, sodium laurate-induced delayed scratching might not involve macrophage-contained histamine because sodium laurate application did not induce the infiltration of inflammatory cells into the skin or increase histamine in the dermis of mast cell-deficient mice and ICR mice.…”

PERK (eIF2α kinase) is required to activate the stress-activated MAPKs and induce the expression of immediate-early genes upon disruption of ER calcium homoeostasis

“…However, the relevant signalling pathways remain to be elucidated. JNK and p38 MAPK are activated by a diverse array of ER stress-inducing agents such as thapsigargin, tunicamycin, and DTT (dithiothreitol), which cause depletion of ER Ca 2+ , inhibition of N-linked glycosylation of proteins, or impairment of disulphide bond formation, respectively [23,[27][28][29][30]. ER stress, for example, is coupled to the activation of stress-activated protein kinases [23,24].…”