Histamine induces proliferation in keratinocytes from patients with atopic dermatitis through the histamine 4 receptor.
BACKGROUND
Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood.


OBJECTIVE
Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes.


METHODS
The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin.


RESULTS
We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan.


CONCLUSIONS
H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.
Division of Immunodermatology and Allergy Research, Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany. Electronic address: Glatzer.Franziska@mh-hannover.de.
Franziska
F
Glatzer
Maria
M
Gschwandtner
Sarah
S
Ehling
Kristine
K
Rossbach
Katrin
K
Janik
Andreas
A
Klos
Wolfgang
W
Bäumer
Manfred
M
Kietzmann
Thomas
T
Werfel
Ralf
R
Gutzmer
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D003876:Dermatitis, Atopic / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D006632:Histamine / Q000276:immunology; D006633:Histamine Antagonists / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010457:Peptidoglycan / Q000276:immunology; D010879:Piperazines / Q000494:pharmacology; D043562:Receptors, G-Protein-Coupled / Q000096:biosynthesis* / Q000235:genetics; D011968:Receptors, Histamine / Q000096:biosynthesis* / Q000235:genetics; D000074040:Receptors, Histamine H4
C418607:HRH4 protein, human; D006633:Histamine Antagonists; C498829:Hrh4 protein, mouse; D007211:Indoles; D008070:Lipopolysaccharides; D010457:Peptidoglycan; D010879:Piperazines; D043562:Receptors, G-Protein-Coupled; D011968:Receptors, Histamine; D000074040:Receptors, Histamine H4; C484309:1-((5-chloro-1H-indol-2-yl)carbonyl)-4-methylpiperazine; D006632:Histamine
4-MH; 4-Methylhistamine; GAPDH; Glyceraldehyde-3-phosphate dehydrogenase; H1R; H2R; H3R; H4R; Histamine; Histamine 1 receptor; Histamine 2 receptor; Histamine 3 receptor; Histamine 4 receptor; Neonatal keratinocyte; Outer root sheath keratinocyte; atopic dermatitis; histamine 4 receptor; human; keratinocyte; mouse; nKC; orsKC; proliferation