Histamine prevents apoptosis in human monocytes


Norito Katoh, Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan.


Background As chronic atopic dermatitis (AD) is associated with activation of circulating and infiltrating monocytes, monocytes are considered to play a pivotal role in the establishment of chronic lesions in AD. Histamine is an important mediator of inflammatory and allergic responses. Although new immunomodulatory functions of histamine have recently become apparent, the effect of histamine on the life span of monocytes remains unclear.

Objective In the present study, we investigated the effect of histamine on the life span of human monocytes from normal healthy donors and patients with AD.

Methods Monocyte apoptosis was induced by serum deprivation, CD95/Fas ligation, or dexamethasone in the presence of histamine, and measured using annexin V-and propidium iodide-staining. Bcl-2 protein and activated caspase-3 were determined by flow cytometry. We also examined the effect of soluble, histamine-induced factors produced by monocytes on apoptosis. Furthermore, we examined whether monocytic apoptosis is dependent on the cAMP pathway.

Results Histamine prevented monocytic apoptosis induced by serum deprivation, CD95/Fas ligation, or dexamethasone in a dose- and time-dependent fashion. The inhibitory effects of histamine on monocytic apoptosis were blocked by an H2R antagonist, and mimicked by an H2R agonist. Histamine also up-regulated the expression of Bcl-2 and Mcl-1, and inhibited the activation of caspase-3. The culture supernatants from histamine-treated monocytes inhibited monocytic apoptosis, which was partly reversed by the removal of IL-10. Monocytes cultured with anti-IL-10 mAb and histamine did not exhibit an inhibitory effect on apoptosis. The histamine-induced anti-apoptotic effect was attenuated when monocytes were cultured in the presence of a cAMP inhibitor.

Conclusions These results indicate that the H2R signals induced by histamine allow monocytes to prolong their life span and infiltrate to the site of inflammation. This process may contribute to the establishment of chronic allergic disorders, such as AD.