Inability of Histamine to Regulate TNF- α Production by Human Alveolar Macrophages

Abstract

Tumor necrosis factor alpha (TNF-alpha), a major product of alveolar macrophages (AM), has been implicated in many pulmonary diseases. Histamine, a mediator important in pulmonary inflammation, has been demonstrated to regulate the production of TNF-alpha by monocytes. In this study, we show that human AM and monocytes differ in their responses to histamine. Whereas histamine suppressed lipopolysaccharide (LPS)-stimulated TNF-alpha production by monocytes through a cAMP-dependent mechanism, it had no effect on either cAMP levels or TNF-alpha production by AM. In contrast, both PGE2 and IL-10 suppressed LPS-stimulated TNF-alpha production by AM and monocytes. The lack of response of AM to histamine appears unique, as histamine suppressed LPS-stimulated TNF-alpha production by mononuclear cells isolated from sites of acute and chronic inflammation, as well as from noninflammatory tissues, and by macrophages differentiated in vitro. In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine, histamine increased cAMP levels in AM. Freshly isolated monocytes and AM did not differ in PDE activity. However, PDE activity in AM, but not in monocytes, was increased 15 min after culture with histamine and may, in part, be responsible for the inability of histamine to suppress TNF-alpha production by AM. However, this increase was small and we hypothesize that additional mechanisms may contribute to the unresponsiveness of AM to histamine. We suggest that the lack of response of AM to histamine may be important in the host defense function of AM in the distal lung.

Importance of Histamine in the Cytokine Network in the Lung Through H2 and H3 Receptors: Stimulation of IL-10 Production

“…Inhibition of TNF release by histamine has been shown in different sources of macrophages, but not in human AMs (39). In that study there was no histamine pretreatment before LPS stimulation, and a higher concentration of LPS was used.…”

“…1b). Interestingly, human AMs release 17 times more TNF than monocytes (34 ng/10 6 AMs and 2 ng/10 6 monocytes) when stimulated with LPS (500 ng/ml), which may explain in part the unresponsiveness of human AMs to histamine inhibition under these conditions (39). In our study LPS (1 ng/ml) stimulated the release of a moderate amount of TNF (0.17 Ϯ 0.08 ng/10 6 cells) from human AMs, which was inhibited by histamine treatment.…”

Evaluation of the anti-inflammatory effects of β-adrenoceptor agonists on human lung macrophages

“…In further studies we wondered whether the endogenous production of PGE 2 might mask responses to -agonists. It is known that macrophages produce PGE 2 in response to LPS and PGE 2 is inhibitory in macrophages (Rowe et al, 1997;Ratcliffe et al, 2007;Buenestado et al, 2012;Birrel et al, 2015). When experiments were performed in the presence of the cyclooxygenase inhibitor, indomethacin, at a concentration known to block PGE 2 production by macrophages completely, there was no improvement in the inhibitory activity of salbutamol.…”

“…Macrophages have been shown to release prostaglandin E 2 (PGE 2 ) following activation with LPS and the addition of exogenous PGE 2 is known to inhibit macrophage responses (Rowe et al, 1997;Ratcliffe et al, 2007;Buenestado et al, 2012). This LPS-induced PGE 2 may act in a paracrine fashion to inhibit macrophage responses and this might interfere with the inhibitory activity of -agonists.…”

Activation of E-prostanoid4and E-prostanoid2receptors inhibits TNF-α release from human alveolar macrophages

“…However, few studies have assessed the effects of such agents on human AMs. PGE 2 -mediated inhibitions of IL-1 [16], IL-8 [17], tumour necrosis factor (TNF)-a [18] and fibronectin [10] have been reported in these cells but the receptor type(s) mediating these responses were not investigated. The aim of the present study was, therefore, to address this issue and by doing so, provide information on the potential efficacy of EP agonists as antiinflammatory drugs for pulmonary diseases, such as chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis or acute respiratory distress syndrome.…”