Cytokine responses of intraepithelial lymphocytes are regulated by histamine H(2) receptor.
BACKGROUND
Histamine participates in the immune regulation of several gastrointestinal diseases. However, the effect of histamine on intestinal intraepithelial lymphocytes (IELs), the front line of the intestinal mucosal immune system, is not well understood. We examined whether histamine has a direct effect on cytokine production by IELs and the involvement of histamine receptor subtypes.


METHODS
Murine IELs were activated by PMA plus ionomycin with/without histamine. Secreted cytokines were measured and compared with those of splenocytes. Intracellular cytokines were detected by flow cytometry. Expression of histamine receptor subtypes in IELs was examined by RT-PCR.


RESULTS
Histamine H(1) receptor (H(1)R), H(2)R, and H(4)R, but not H(3)R mRNA were expressed on IELs. Histamine significantly decreased Th1-cytokine (IFN-gamma, TNF-alpha, and IL-2) and also IL-4 production in IELs as well as splenocytes. The selective H(2)R antagonist famotidine, but not the H(1)R antagonist pyrilamine nor the H(3)R/H(4)R antagonist thioperamide, competes with the inhibitory effect of histamine on these cytokine production in IELs. These suppressive effects of histamine were mimicked by a selective H(2)R/H(4)R agonist dimaprit. Further, these suppressive effects of histamine for Th1-cytokine and IL-4 did not accompany the enhancement of IL-10 production or IL-10 mRNA level in IELs. Intracellular cytokine analysis revealed that the number of IFN-gamma-producing alphabeta T cells was significantly reduced by histamine in IELs.


CONCLUSIONS
Histamine has a direct suppressive effect on IEL-derived cytokines via H(2)R, which would have a crucial role in the suppression of local immunoregulation in the intestinal epithelium.
Takagaki
Kosuke
K
First Department of Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Higashi-ku, Hamamatsu, 431-3192, Japan.
Osawa
Satoshi
S
Horio
Yoshiaki
Y
Yamada
Takanori
T
Hamaya
Yasushi
Y
Takayanagi
Yasuhiro
Y
Furuta
Takahisa
T
Hishida
Akira
A
Ikuma
Mutsuhiro
M
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D005434:Flow Cytometry; D015870:Gene Expression; D006632:Histamine / Q000008:administration & dosage* / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D015759:Ionomycin / Q000494:pharmacology; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D012333:RNA, Messenger / Q000378:metabolism; D011968:Receptors, Histamine / Q000187:drug effects / Q000378:metabolism; D011970:Receptors, Histamine H2 / Q000187:drug effects / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016207:Cytokines; D012333:RNA, Messenger; D011968:Receptors, Histamine; D011970:Receptors, Histamine H2; D015759:Ionomycin; D006632:Histamine; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate