The pleiotropic effects of histamine are mediated by 4 histamine receptors (HRs), H1R, H2R, H3R, and H4R, which are G protein-coupled receptors.
H1R is expressed in various cell types, such as neurons, endothelial cells, adrenal medulla, muscle cells, hepatocytes, chondrocytes, monocytes, neutrophils, eosinophils, DCs, T cells, and B cells.
Signaling via H1R leads to the activation of intracellular transcription factors, such as IP3 (inositol triphosphate), PLC (phospholipase C), PKC (protein kinase C), DAG (diacylglycerol), and [Ca.sup.2+].
H2R antagonizes some of the effects mediated by H1R and leads to the relaxation of smooth muscle cells, causing vasodilation.
Histamine has been shown to regulate T cells by enhancing Th1-type responses through the H1R
and downregulating both the Th1 and Th2 type responses through the H2R [15, 16].
Upregulated expression of H1R was shown in MS lesions , whereas epidemiological studies demonstrated a protective effect of H1R antagonists capable to cross the BBB in MS .
Although H1R and H2R have a clear pro-inflammatory role and disease-promoting effect, H1R and H2R activation may also play an important role in limiting autoimmune responses .
Ligation of the histamine receptor, H1R, on immune cells induces secretion of pro-inflammatory cytokines, such as IL-1[beta], IL-6, IL-8, and the chemokine CCL5 .
In the three substantive texts of the play, when in 4.5 Laertes breaks in, the stage directions read as follows: "Enter Laertes with others' (Q2, L1r; 4.5.111); 'Enter Laertes" (F1, TLN 2851); 'enter Laertes' (Q1, H1r
(28) Anon., Alphonsus of Germany (1654; Wing: C1952), H1r
(18) William Struther, SCOTLANDS WARNING, Or a Treatise of Fasting (Edinburgh, 1628; STC: 23370), 60; Juan Luis Vives, The Instructio[n] of a Christen Woma[n], Richarde Hyrd (trans) (London, 1529; STC: 24856), H1r
; Phillip [sic] Stubbes, [A Christal Glasse for Christian Women] (London, 1591; STC: 23381), A3r.
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