Histamine receptor 2 modifies dendritic cell responses to microbial ligands Remo Frei, PhD, Ruth Ferstl, PhD, Patrycja Konieczna, MSc, Mario Ziegler,

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Histamine receptor 2 modifies dendritic cell responses to microbial ligands Remo Frei, PhD, Ruth Ferstl, PhD, Patrycja Konieczna, MSc, Mario Ziegler, Dipl-Ing, Tunde Simon, PhD, Tulia Mateus Rugeles, MSc, Susanne Mailand, MSc, Takeshi Watanabe, MD, PhD, Roger Lauener, MD, Cezmi A. Akdis, MD, Liam O'Mahony, PhD Journal of Allergy and Clinical Immunology Volume 132, Issue 1, Pages 194-204.e12 (July 2013) DOI: 10.1016/j.jaci.2013.01.013 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Histamine modulates cytokine secretion from TLR-stimulated DCs. A, Human MDDCs secreted less TNF-α, IL-12p70, and CXCL10 after LPS stimulation, whereas IL-10 secretion was increased, in the presence of histamine. B, MDDCs stimulated with Pam3Cys and histamine resulted in decreased TNF-α and enhanced IL-10 secretion. C and D, LPS-stimulated TNF-α secretion from mDCs was suppressed by histamine (Fig 1, C), whereas IFN-α gene expression in CpG-stimulated pDCs was also suppressed by histamine coincubation (Fig 1, D). Each line represents an individual donor. EF1α, Elongation factor 1α. ∗P < .05, ∗∗P < .01, and ∗∗∗P < .001. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Histamine suppresses TH1 lymphocyte polarization. A and B, Lymphocytes secreted IFN-γ and expressed T-box transcription factor (T-bet) after coculture with LPS-stimulated MDDCs. However, coculture of MDDCs with histamine significantly reduced IFN-γ secretion (Fig 2, A) and T-bet expression (Fig 2, B). C, GATA-3 and Foxp3 expression were not significantly altered. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Histamine suppresses TLR-induced NK-κB and AP-1 activation. A, THP-1 cells stimulated with LPS in the presence of histamine displayed reduced NF-κB/AP-1 activity compared with that seen in cells stimulated with LPS alone. B, Histamine reduces TLR-induced NF-κB phosphorylation in MDDCs. MFI, Mean fluorescence intensity. C, Phosphorylation and degradation of IκB were unaltered by histamine coincubation. β-Actin staining is the loading control. D, Phosphorylation of p38, c-Jun N-terminal kinase (JNK), and c-Jun was significantly suppressed by histamine. ∗P < .05 and ∗∗P < .01. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Histamine-associated signaling cascades. A, Inhibition of mammalian target of rapamycin signaling by rapamycin and histone deacetylation by trichostatin in MDDCs abrogated histamine-induced upregulation of IL-10, with no effect on histamine-induced suppression of TNF-α, IL-12, or CXCL10 (n = 8 donors). B, Neither of the phosphoinositide 3-kinase inhibitors altered the effects of histamine on IL-10, TNF-α, IL-12, or CXCL10 secretion. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 H2R is responsible for the histamine modulatory effects. A, MDDCs express gene transcripts for H1R, H2R, and H4R. B, Suppression of THP-1 cell NF-κB/AP-1 activation by histamine was blocked by an H2R antagonist and replicated by an H2R agonist. C, The H2R antagonist famotidine also reversed the histamine-induced suppression of MDDC TNF-α secretion. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 H2R intracellular signaling requires cAMP and Epac. A, Histamine increased cAMP levels in MDDCs through H2R. B and C, Histamine-associated suppression of LPS-induced MDDC TNF-α (Fig 6, B) and IL-12 (Fig 6, C) secretion was replicated by the cAMP inducer forskolin or exogenous cAMP and was improved by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). D, The PKA inhibitor H-89 had no effect on cytokine secretion. E, Epac activation reduced TNF-α, IL-12, and CXCL10 secretion from LPS-stimulated MDDCs but did not significantly enhance IL-10 secretion. F, Inhibition of Rap1 signaling by GGTI298 in MDDCs abrogated histamine-induced upregulation of IL-10. ∗P < .05 (n = 4 donors). Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 7 Differential effects of L rhamnosus administration to wild-type and H2R knockout (KO) mice. Oral administration of L rhamnosus to wild-type animals (n = 10) significantly reduces Peyer patch cytokine secretion, which was not observed in H2R knockout animals (n = 8). Results are expressed as means plus SEMs before (day 0) and after (day 9) feeding. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 8 Schematic representation of H2R and TLR pathway interactions. AC, Adenylate cyclase; JNK, c-Jun N-terminal kinase. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Histamine dose response for LPS-stimulated MDDCs. LPS-stimulated TNF-α secretion and IL-12 secretion were both significantly suppressed by histamine at 1 × 10−4 mol/L, 1 × 10−5 mol/L, and 1 × 10−6 mol/L, whereas suppression was no longer significant for IL-12 at 1 × 10−7 mol/L. Results are represented as means ± SEs (n = 4 donors). ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Histamine alters cytokine gene expression from LPS-stimulated MDDCs. LPS-stimulated IL-12p35, IL-12p40, TNF-α, CXCL9, CXCL10, and CXCL11 gene expression is significantly reduced by histamine, and IL-10 gene expression is increased 4 hours after stimulation. Each line represents an individual donor. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Modification of TNF-α, but not IL-10, gene expression does not require new protein synthesis. Histamine suppression of LPS-stimulated TNF-α gene expression was unaltered by cycloheximide. However, IL-10 gene expression did not increase when cycloheximide was present. Each line represents an individual donor. EF1α, Elongation factor 1α. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Histamine alters mDC cytokine secretion. A and B, Histamine suppression of Pam3Cys-stimulated TNF-α secretion by mDCs (Fig E4, A) was associated with enhanced secretion of IL-10 (Fig E4, B). C, In contrast, histamine did not alter CpG-induced IL-10 gene expression in pDCs. EF1α, Elongation factor 1α. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Histamine suppresses NF-κB/AP-1 activation. Histamine (1 × 10−5 mol/L) significantly reduces NF-κB/AP-1 activation in response to Pam3Cys, gram-positive bacteria (Streptococcus pyogenes), and gram-negative bacteria (P aeruginosa). Results are represented as means ± SEs (n = 4 replicates per condition). ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Histamine suppresses Pam3Cys-induced AP-1 activation. Phosphorylation of p38 and c-Jun N-terminal kinase (JNK) mitogen-activated protein kinase were significantly suppressed by histamine in Pam3Cys-stimulated MDDCs, as was phosphorylation of c-Jun. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E7 MDDCs express H1R, H2R, and H4R. A, MDDC expression of histamine receptors was determined by using flow cytometry. A greater percentage of MDDCs expressed H2R compared with H1R or H4R. B, After stimulation with LPS for 4 or 8 hours, H1R and H4R gene expression was significantly decreased, whereas H2R gene expression was significantly increased at the 8-hour time point. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E8 H2R suppression of NF-κB/AP-1 is cAMP dependent. Histamine-associated suppression of LPS-induced NF-κB/AP-1 activation was replicated by the cAMP inducer forskolin or exogenous cAMP and was improved by the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The PKA inhibitor H-89 had no effect. ∗P < .05. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E9 NF-κB/AP-1 is associated with Epac, but not PKA, activity. Histamine suppresses NF-κB/AP-1 activation in THP-1 cells at 4, 6, and 20 hours after LPS stimulation. The PKA inhibitor H-89 did not significantly block the suppressive effect of histamine on NF-κB/AP-1 activity, whereas stimulation with the Epac agonist 8-CPT-cAMP replicated the effects of histamine. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E10 L rhamnosus secretes histamine. L rhamnosus expresses histidine decarboxylase (HDC; lanes A and B), whereas an unrelated Bifidobacterium longum strain does not express HDC (lanes C and D). L rhamnosus also secretes histamine when histidine is present in the culture medium. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E11 Differential effects of L rhamnosus administration to wild-type and H2R knockout mice. Oral administration of L rhamnosus to wild-type animals (n = 10) significantly reduces PMA/ionomycin-stimulated Peyer patch cytokine secretion, which was not observed in H2R knockout animals (n = 8). Results are expressed as means plus SEMs before (day 0) and after (day 9) feeding. Journal of Allergy and Clinical Immunology 2013 132, 194-204.e12DOI: (10.1016/j.jaci.2013.01.013) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions