The influence of histamine on precursors of granulocytic leukocytes in murine bone marrow

doi:10.1016/0024-3205(88)90430-4

Life Sciences

Volume 42, Issue 9, 1988, Pages 999-1010

https://doi.org/10.1016/0024-3205(88)90430-4 Get rights and content

Abstract

The effect of histamine on granulocytic progenitor cells in murine bone marrow was studied in vitro. When bone marrow cells were cultured for three days with the drug, 10⁻⁸ M to 10⁻⁵ M of histamine stimulated differentiation and proliferation of myeloid precursor cells. Subsequently, the number of descendant cells, such as metamyelocytes and neutrophils, increased dose-dependently. Co-existence of equimolar H₂ blockers such as cimetidine and ranitidine completely suppressed this effect of histamine, though this was not the case with an H₁ blocker/histamine combination. Significant increase in ³H-thymidine incorporation was observed almost exclusively in myeloblasts, promyelocytes and myelocytes after exposure to histamine at concentrations higher than 10⁻⁸ M. Also, selective incorporation of ³H-histamine into bone marrow cells was observed in myeloblasts and promyelocytes, but histamine incorporation was not influenced by the presence of either of histamine agonists or antagonists. While histamine, via H₂ receptors, selectively increased the number of granulocytic colony forming units in culture (CFU-C), it had no such effect on macrophage colonies. Considering these findings, it was concluded that histamine promotes proliferation and differentiation of granulocytic myeloid cells via 1) H₂ receptors in the CFU-C stage and 2) histamine receptors which are neither H₁ nor H₂ in the stages of myeloblast and promyelocyte differentiation.

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Cited by (56)

Antihistaminergics and inverse agonism: Potential therapeutic applications
2013, European Journal of Pharmacology
Citation Excerpt :
The H4 receptor is prominently expressed in medullary and peripheral hematopoietic cells, namely eosinophils, neutrophils and CD4+ T cells (Zhu et al., 2001). The H4 receptor is involved in histamine-induced increases in intracellular calcium in human eosinophils (Raible et al., 1994), facilitating terminal myeloblast and promonocyte differentiation (Nakaya and Tasaka, 1988). Until now, the most clinically relevant uses of histamine receptor ligands are achieved through the regulation of H1 or H2 receptors, which are widely expressed in most tissues (Bakker et al., 2002).
The accurate characterization of the molecular mechanisms involved in the action of receptor ligands is important for their appropriate therapeutic use and safety. It is well established that ligands acting at the histamine system currently used in the clinic exert their actions by specifically antagonizing G-protein coupled H₁ and H₂ receptors. However, most of these ligands, assumed to be neutral antagonists, behave as inverse agonists displaying negative efficacy in experimental systems. This suggests that their therapeutic actions may involve not only receptor blockade, but also the decrease of spontaneous receptor activity. The mechanisms whereby inverse agonists achieve negative efficacy are diverse. Theoretical models predict at least three possible mechanisms, all of which are supported by experimental observations. Depending on the mechanism of action engaged, the inverse agonist could interfere specifically with signaling events triggered by unrelated receptors. This possibility opens up new venues to explain the therapeutic actions of inverse agonists of the histamine receptor and perhaps new therapeutic applications.
Histamine-cytokine connection in immunity and hematopoiesis
2004, Cytokine and Growth Factor Reviews
A number of recent studies have led to a reappraisal of the functional capacities of histamine in immunity and hematopoiesis. This change of perspective was provided by the following findings: (1) the evidence for multiple cellular sources of histamine, differing from mature basophils and mast cells by their ability to newly synthesize and liberate the mediator without prior storage, (2) the discovery of a novel histamine receptor (H₄R), preferentially expressed on hematopoietic and immunocompetent cells, (3) the potential intracellular activity of histamine through cytochrome P450 and (4) the demonstration of a histamine–cytokine cross-talk. Indeed, cytokines not only modulate the degranulation process of histamine but also control its neosynthesis by the histamine-forming enzyme, histidine decarboxylase (HDC), at transcriptional and post-transcriptional levels. In turn, histamine intervenes in the intricate cytokine network, regulating cytokine production by immune cells through distinct receptors signaling distinct biological effects. This type of regulation is particularly relevant in the context of TH1/TH2 differentiation, autoimmunity and tumor immunotherapy.
Trends in histamine research: New functions during immune responses and hematopoiesis
2002, Trends in Immunology
Histamine is a bioamine with multiple physiological activities. In the immune system, it not only mediates the deleterious effects accompanying allergic reactions, but it acts also in a more subtle way by modulating the T helper 1 (Th1)–Th2 balance and possibly hematopoiesis. The histamine required for Th-cell polarization is provided by mast cell or basophil degranulation, as well as being newly synthesized and immediately released by other hematopoietic cells, in response to molecules generated during the immune response. Its global effect depends on the subtype and distribution of histamine receptors on target cells. The recent discovery of a novel H₄ receptor, which is expressed preferentially on immunocompetent cells, will have important consequences for the understanding of the regulatory functions of histamine during the immune response.
Histamine stimulates production of osteoclast differentiation factor/receptor activator of nuclear factor-κB ligand by osteoblasts
2002, Biochemical and Biophysical Research Communications
Histamine $H_{1}, H_{2}$ , and H₃ receptors are expressed by osteoblastic MC3T3-E1 (E1) cells derived from mouse calvaria. Expression of the osteoclast differentiation factor (ODF)/receptor activator of nuclear factor-κB ligand (RANKL) transcript was induced in E1 cells and bone marrow stromal cells (ST2). Histamine markedly increased the steady-state level of ODF/RANKL mRNA in a dose-dependent manner. The effect of histamine on expression of ODF/RANKL mRNA by E1 cells was transient, with a peak at 6 h. Western blot analysis revealed that histamine increased production of ODF/RANKL protein by E1 cells at 12 h. In cocultures of E1 cells and mouse bone marrow cells, histamine stimulated osteoclastogenesis in the presence of 1,25-dihydroxyvitamin D₃ and this effect was blocked by preincubation with neutralizing antibody against ODF/RANKL. These results suggest that histamine regulates osteoclastogenesis, at least in part, through induction of ODF/RANKL expression by osteoblasts and bone marrow stromal cells.
Short-term prevention of osteoclastic resorption and osteopenia in ovariectomized rats treated with the H<inf>2</inf> receptor antagonist cimetidine
2002, Bone
Citation Excerpt :
This likely explains the absence of detectable mast cell degranulation in ovx rats.17 Histamine is a potent mitogen, particularly for hematopoietic stem cells,1,24,33 through H2 receptors.3,21 Histamine also modulates hematopoietic cell differentiation.15,34
Ovariectomy rapidly induces strong osteoclast differentiation, leading to a marked loss of cancellous bone in the rat appendicular skeleton. As we found that histamine inhibition prevented periosteal bone resorption in rats, we tested the hypothesis that cimetidine, an H₂ receptor antagonist, prevents the osteoclastic burst and subsequent trabecular bone loss in this setting. Forty female Sprague-Dawley rats were ovariectomized (ovx) or sham-operated. Rats from each group received daily intramuscular injections of cimetidine (125 mg/kg per day) or vehicle. The animals were killed 14 days after surgery, and their femora were processed for morphometry. Cimetidine had no effect on serum estradiol levels in the control and ovx rats. BV/TV was reduced by 36% in the ovx rats, and by 10% in the cimetidine treated rats (p < 0.01). Tb.N and Tb.Wi were significantly reduced by 30% in the ovx rats and by 15% ovx-treated ones. OcS/BS did not change in the treated ovx rats, but increased 3.7-fold in the untreated ovx ones (p < 0.001). The N.Oc/TBPm increased markedly in the ovx rats (2.6-fold, p < 0.0001 vs. controls), but only slightly in the cimetidine-treated animals (+18%, p < 0.05 vs. controls), with a significant difference between the cimetidine-treated and -untreated ovx animals (p < 0.001). Cimetidine had no effect on these parameters in sham-operated animals. These results show that histamine inhibition by an H₂ receptor antagonist partially prevents the consequences of castration on cancellous bone, possibly by an action on osteoclast differentiation. Interestingly, cimetidine had no effect on basal resorption along trabecular bone. Histamine inhibition by H₂ blockers warrants further investigation in this model of osteopenia.
Modulation of cisplatin pharmacodynamics by Cremophor EL: Experimental and clinical studies
2002, European Journal of Cancer
Citation Excerpt :
The induction of histamine release may also play a role in the haematopoietic response to CrEL administration [25–27] . Histamine is known to trigger colony forming units into the cell cycle stimulate the proliferation of committed haematopoietic progenitor cells [28,29], and modulate the response of primitive haematopoietic cells to interleukin-3 [30,31]. In mice, no evidence was obtained of localised toxicity or marrow destruction as a result of CrEL injection [24], which is consistent with flow cytometric studies demonstrating that even very high concentrations of CrEL (>10%) did not lyse mammalian cell membranes [32].
The paclitaxel vehicle Cremophor EL (CrEL) has been shown to selectively inhibit the accumulation of cisplatin in peripheral blood leucocytes, but not in tumour cells in vitro, and we hypothesised that this phenomenon is responsible for the improvement of the therapeutic index of cisplatin observed in combination studies with paclitaxel. Here, we report on studies assessing the interaction between CrEL and cisplatin in a murine model, and involving the potential clinical applicability of CrEL as a protector for cisplatin-associated haematological side-effects. In mice, CrEL (0.17 ml/kg, intravenous (i.v.)) given in combination with cisplatin (10 mg/kg, intraperitoneal (i.p.)) did not change the pharmacokinetics of cisplatin. Cisplatin-induced haematological toxicity, expressed as white blood cells (WBC) at nadir, was significantly reduced by CrEL from 5.05±0.95 to 6.50±1.31×10⁹/l (P=0.0009). Data obtained from cancer patients treated with cisplatin (70 mg/m², 3-h i.v.) and topotecan (0.45 or 0.60 mg/m²/day×2) preceded by CrEL (12 ml, 3-h i.v.) (n=6) or without CrEL (n=10) similarly indicated significant differences in the percent decrease in WBC between the groups (46.5±18.7 versus 67.2±15.0%; P=0.029). Likewise, the percent decrease in platelet count was significantly greater in the absence of CrEL (23.9±5.38 versus 73.3±15.5%; P=0.0003). Pharmacokinetic parameters of unbound and total cisplatin and of topotecan lactone and total drug were not significantly different from historic control values (P⩾0.245). Overall, this study provides further evidence on the important role of CrEL in the pharmacological and toxicological profile of cisplatin, and implies that reformulation of cisplatin with CrEL for systemic treatment might achieve an improvement of its therapeutic index, particularly in the setting of a weekly dose-dense concept.

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The influence of histamine on precursors of granulocytic leukocytes in murine bone marrow

Abstract

Blood

J. Immunol. Methods

Exp. Cell Res.

Cancer

Aust. J. Exp. Biol. Med. Sci.

Arch. int. Pharmacodyn.

Fedn. Proc.

J. Physiol. (London)

Agents actions

Br. J. Med.

Lancet