title: Inhibition of human primary melanoma cell proliferation by histamine is enhanced by interleukin-6.
abstract: BACKGROUND
  Interleukin-6 (IL-6) is a bifunctional growth factor in malignant melanoma; its expression increases during the malignant progression of the disease. Histamine, detected in large amounts in normal and pathological proliferating tissues, is an important paracrine and autocrine regulator of normal and tumour cell proliferation as well.
  
  
  METHODS
  We investigated the presence and function of IL-6 and histamine in the WM35 primary human melanoma cell line with respect to their direct role in cell proliferation and their regulatory interactions.
  
  
  RESULTS
  IL-6 inhibited the proliferation of WM35 melanoma cells and increased significantly the expression of histidine decarboxylase as well as histamine production. It had dose-dependent effects on the proliferation: high concentration (10-5 M) was inhibitory through H1 histamine receptors while low histamine concentration acting on H2 receptors, with a simultaneous increase of cAMP, enhanced colony formation in the monolayer. Furthermore, IL-6 increased the H1- but decreased the H2-histamine receptor expression of the melanoma cells. On the other hand, histamine was locally synthesized by the WM35 melanoma cells.
  
  
  CONCLUSIONS
  We suggest that the growth arrest induced by IL-6 is in part mediated by its dual action on histamine: a shift toward H1 receptor predominance and an elevation of locally produced histamine with prevalent action on the inhibitory response triggered through the H1 receptor. These findings suggest a local cross-talk between histamine and IL-6 in the regulation of melanoma growth.
authors.affiliation: Semmelweis University, Budapest, Hungary.
authors.forename: E
authors.initials: E
authors.lastname: Lázár-Molnár
authors.forename: H
authors.initials: H
authors.lastname: Hegyesi
authors.forename: E
authors.initials: E
authors.lastname: Pállinger
authors.forename: P
authors.initials: P
authors.lastname: Kovács
authors.forename: S
authors.initials: S
authors.lastname: Tóth
authors.forename: C
authors.initials: C
authors.lastname: Fitzsimons
authors.forename: G
authors.initials: G
authors.lastname: Cricco
authors.forename: G
authors.initials: G
authors.lastname: Martin
authors.forename: R
authors.initials: R
authors.lastname: Bergoc
authors.forename: Z
authors.initials: Z
authors.lastname: Darvas
authors.forename: E S
authors.initials: ES
authors.lastname: Rivera
authors.forename: A
authors.initials: A
authors.lastname: Falus
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D003994:Bucladesine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015870:Gene Expression / Q000187:drug effects; D006146:Guanidines / Q000494:pharmacology; D006632:Histamine / Q000627:therapeutic use*; D006634:Histamine H1 Antagonists / Q000378:metabolism; D006635:Histamine H2 Antagonists / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015850:Interleukin-6 / Q000627:therapeutic use*; D007546:Isoquinolines / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy*; D016133:Polymerase Chain Reaction / Q000379:methods; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012878:Skin Neoplasms / Q000188:drug therapy*; D013449:Sulfonamides; D014407:Tumor Cells, Cultured
chemical_list: D004791:Enzyme Inhibitors; D006146:Guanidines; D006634:Histamine H1 Antagonists; D006635:Histamine H2 Antagonists; D007093:Imidazoles; D015850:Interleukin-6; D007546:Isoquinolines; D019947:Receptors, Interleukin-6; D013449:Sulfonamides; D005576:Colforsin; D015124:8-Bromo Cyclic Adenosine Monophosphate; D003994:Bucladesine; D006632:Histamine; C060591:arpromidine; D017868:Cyclic AMP-Dependent Protein Kinases; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide