Abstract
Advanced glycation end products (AGEs) are modifications of proteins/lipids that become nonenzymatically glycated after contact with aldose sugars. Among various subtypes of AGEs, glyceraldehyde-derived AGE (AGE-2) and glycolaldehyde-derived AGE (AGE-3) are suggested to play roles in inflammation in diabetic patients. Because the engagement of intercellular adhesion molecule (ICAM)-1, B7.1, B7.2, and CD40 on monocytes with their ligands on T cells plays roles in cytokine production, we examined the effects of AGE-2 and AGE-3 on the expression of adhesion molecules and cytokine production in human peripheral blood mononuclear cells (PBMC) and their modulation by histamine in the present study. AGE-2 and AGE-3 induced the expressions of ICAM-1, B7.1, B7.2, and CD40 on monocytes and the production of interferon-γ in PBMC. Histamine concentration-dependently inhibited the action of AGE-2 and AGE-3. The effects of histamine were antagonized by an H2 receptor antagonist, famotidine, and mimicked by H2/H4 receptor agonists dimaprit and 4-methylhistamine. Histamine induced cAMP production in the presence and absence of AGE-2 and AGE-3. The effects of histamine were reversed by a protein kinase A (PKA) inhibitor, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline (H89), and mimicked by a dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicated that histamine inhibited the AGE-2- and AGE-3-induced adhesion molecule expression and cytokine production via H2 receptors and the cAMP/PKA pathway.
Footnotes
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This work was supported in part by grants from the Japan Society for the Promotion of Science [Grants 18590509, 20590539, 17659159, 19659061, 21659141, 21390071, 215905694]; the Scientific Research from Ministry of Health, Labour and Welfare of Japan; and the Takeda Science Foundation.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.109.155960.
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ABBREVIATIONS: AGE, advanced glycation end product; RAGE, receptor for advanced glycation end product(s); IFN, interferon; PBMC, peripheral blood mononuclear cell(s); ICAM, intercellular adhesion molecule; H, histamine; PKA, protein kinase A; IL, interleukin; 4-MH, 4-methylhistamine dihydrochloride; BSA, bovine serum albumin; dbcAMP, dibutyryl cAMP; H89, N-[2-(4-bromocinnamylamino)ethyl]-5-isoquinoline; FITC, fluorescein isothiocyanate; mAb, monoclonal antibody; Ab, antibody; ELISA, enzyme-linked immunosorbent assay; sRAGE, soluble advanced glycosylation end product(s); LPS, lipopolysaccharide; NF-κB, nuclear factor-κB; SN50, H-Ala-Ala-Val-Ala-Leu-Leu-Pro-Ala-Val-Leu-Leu-Ala-Leu-Leu-Ala-Pro-Val-Gln-Arg-Lys-Arg-Gln-Lys-Leu-Met-Pro-OH; HDC, histidine decarboxylase.
- Received May 11, 2009.
- Accepted June 26, 2009.
- The American Society for Pharmacology and Experimental Therapeutics
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Histamine Inhibits Advanced Glycation End Products-Induced Adhesion Molecule Expression on Human Monocytes
