Prue H. Hart

The water-soluble components of the essential oil of Melaleuca alternifolia (tea tree oil) suppress the production of superoxide by human monocytes, but not neutrophils, activated in vitro

Abstract:Objective: To evaluate the regulatory properties of the essential oil of Melaleuca alternifolia (tea tree oil) on the production of oxygen derived reactive species by human peripheral blood leukocytes activated in vitro.¶Materials and methods: The ability of tea tree oil to reduce superoxide production by neutrophils and monocytes stimulated with N-formyl-methionyl-leucyl-phenylalanine (fMLP), lipopolysaccharide (LPS) or phorbol 12-myristate 13-acetate (PMA) was examined.¶Results: The water-soluble fraction of tea tree oil had no significant effect on agonist-stimulated superoxide production by neutrophils, but significantly and dose-dependently suppressed agonist-stimulated superoxide production by monocytes. This suppression was not due to cell death. Chemical analysis identified the water-soluble components to be terpinen-4-ol, α-terpineol and 1,8-cineole. When examined individually, terpinen-4-ol significantly suppressed fMLP- and LPS- but not PMA-stimulated superoxide production; α-terpineol significantly suppressed fMLP-, LPS- and PMA-stimulated superoxide production; 1,8-cineole was without effect.¶Conclusion: Tea tree oil components suppress the production of superoxide by monocytes, but not neutrophils, suggesting the potential for selective regulation of cell types by these components during inflammation.¶

Tea tree oil reduces histamine-induced skin inflammation

Summary Background  Tea tree oil is the essential oil steam‐distilled from Melaleuca alternifolia , an Australian native plant. In recent years it has become increasingly popular as an antimicrobial for the treatment of conditions such as tinea pedis and acne.

Differential responses of human monocytes and macrophages to IL-4 and IL-13.

The primary interleukin‐4 (IL‐4) receptor complex on monocytes (type I IL‐4 receptor) includes the 140‐kDa α chain (IL‐4Rα) and the IL‐2 receptor γ chain, γc, which heterodimerize for intracellular signaling, resulting in suppression of lipopolysaccharide (LPS)‐inducible inflammatory mediator production. The activity of IL‐13 on human monocytes is very similar to that of IL‐4 because the predominant signaling chain (IL‐4Rα) is common to both receptors. In fact, IL‐4Rα with IL‐13Rα1 is designated both as an IL‐13 receptor and the type II IL‐4 receptor. When the anti‐inflammatory activities of IL‐4 and IL‐13 were investigated on synovial fluid macrophages and compared with the responses by monocytes isolated from the patients at the same time as joint drainage, the response profiles differed with some responses similar in the two cell populations, others reduced on the inflammatory cells. Similar differences were recorded in the response profiles to IL‐4 and IL‐13 by monocytes and monocytes cultured for 7 days in macrophage colony‐stimulating factor (M‐CSF) or granulocyte‐macrophage CSF (GM‐CSF) (monocyte‐derived macrophages, MDMac). MDMac have reduced γc mRNA levels and reduced expression of the functional 64‐kDa γc. There was a similar loss of IL‐13Rα1 mRNA on monocyte differentiation. In turn, there was a significant reduction in the ability of IL‐4 and IL‐13 to activate STAT6. These findings suggest that different functional responses to IL‐4 and IL‐13 by human monocytes and macrophages may result from reduced expression of γc and IL‐13Rα1. J. Leukoc. Biol. 66: 575–578; 1999.

Cis‐UROCANIC ACID SYNERGIZES WITH HISTAMINE FOR INCREASED PGE2 PRODUCTION BY HUMAN KERATINOCYTES: LINK TO INDOMETHACIN‐INHIBITABLE UVB‐INDUCED IMMUNOSUPPRESSION

Abstract— There is considerable evidence that suppression of the immune system by UVB (280–320 nm UV) irradiation is initiated by UVB‐dependent isomerization of a specific skin photoreceptor, urocanic acid (UCA), from the trans to the cis form. Previous studies have confirmed that cis‐UCA administration to mice 3–5 days prior to hapten sensitization at a distant site, suppresses the contact hypersensitivity (CHS) response upon challenge. This study demonstrates in mice that cis‐UCA, like UVB, suppresses CHS to trinitrochlorobenzene by a mechanism partly dependent on prostanoid production. In vitro experimentation showed that human keratinocytes, isolated from neonatal foreskin, increased prostaglandin E2 (PGE2) production in response to histamine but not UCA alone. However, cis‐UCA synergized with histamine for increased PGE2 production by keratinocytes. cis‐urocanic acid also increased the sensitivity of keratinocytes for PGE2 production in response to histamine. Prostaglandin E2 from keratinocytes exposed to cis‐UCA and histamine may contribute directly, or indirectly, to the regulation of CHS responses by UVB irradiation.

Histamine involvement in UVB- and cis-urocanic acid-induced systemic suppression of contact hypersensitivity responses

Studies in experimental models have implicated histamine and prostanoids in ultra‐violet B (UVB)‐ and cis‐urocanic acid (UCA)‐induced systemic immunosuppression. This study examined he hypothesis that UVB irradiation and cis‐UCA suppressed contact hypersensitivity responses to hapten by induction of histamine, which in turn evoked a prostanoid‐dependent component of immunosuppression. BALB/c mice were administered with a cis‐UCA monoclonal antibody, a combination of histamine types 1 and 2 receptor antagonists, or indomethacin. Mice were sensitized to 2,4,6‐trinitrochlorobenzene (TNCB) on their ventral surface 5 days after UVB irradiation, or cis‐UCA or histamine administration. Ears were challenged with TNCB 5 days later. Cis‐UCA antibody inhibited the suppressive effects of UVB by approximately 60% and confirmed that suppression of contact hypersensitivity responses by UVB was due, at least in part, to mechanisms involving cis‐UCA. Histamine suppressed contact hypersensitivity responses and the effects of cis‐UCA and histamine were not cumulative, suggesting that cis‐UCA and histamine signal largely through the same pathway. The immunosuppressive effects of histamine were not affected by the cis‐UCA antibody, consistent with the model that histamine acts downstream of cis‐UCA. Administration of histamine receptor antagonists and indomethacin each approximately halved the UVB‐ and cis‐UCA‐induced systemic suppression of contact hypersensitivity responses. The effects of the reagents that inhibited the action of histamine and prevented prostanoid production were not cumulative, and suggested involvement in the same pathway. These results support the involvement of cis‐UCA, histamine and prostanoids, in a sequence, in UVB‐induced systemic suppression of contact hypersensitivity responses.

Sunlight, Immunosuppression And Skin Cancer: Role Of Histamine And Mast Cells

1. The development into tumours of skin cells transformed by ultraviolet (UV) B radiation of wavelengths 290–320 nm is enhanced by the ability of UVB to suppress an immune response that would otherwise destroy them. Ultraviolet B‐induced immunomodulation may be by multiple mechanisms, but generally manifests in an antigen‐presenting cell defect and an altered cytokine environment in the draining lymph nodes.

Mast cells, neuropeptides, histamine, and prostaglandins in UV-induced systemic immunosuppression.

There is a direct correlation between dermal mast cell prevalence in dorsal skin of different mouse strains and susceptibility to UVB-induced systemic immunosuppression; highly UV-susceptible C57BL/6 mice have a high dermal mast cell prevalence while BALB/c mice, which require considerable UV radiation for 50% immunosuppression, have a low mast cell prevalence. There is also a functional link between the prevalence of dermal mast cells and susceptibility to UVB- and cis-urocanic acid (UCA)-induced systemic immunosuppression. Mast cell-depleted mice are unresponsive to UVB or cis-UCA for systemic immunosuppression unless they are previously reconstituted at the irradiated or cis-UCA-administered site with bone marrow-derived mast cell precursors. cis-UCA does not stimulate mast cell degranulation directly. Instead, in support of studies showing that neither UVB nor cis-UCA was immunosuppressive in capsaicin-treated, neuropeptide-depleted mice, cis-UCA-stimulated neuropeptide release from sensory c-fibers which, in turn, could efficiently degranulate mast cells. Studies in mice suggested that histamine, and not tumor necrosis factor alpha (TNF-alpha), was the product from mast cells that stimulated downstream immunosuppression. Histamine receptor antagonists reduced by approximately 60% UVB and cis-UCA-induced systemic immunosuppression. Indomethacin administration to mice had a similar effect which was not cumulative with the histamine receptor antagonists. Histamine can stimulate keratinocyte prostanoid production. We propose that both histamine and prostaglandin E(2) are important in downstream immunosuppression; both are regulatory molecules supporting the development of T helper 2 cells and reduced expression of type 1 immune responses such as a contact hypersensitivity reaction.

Tea tree oil reduces histamine-induced oedema in murine ears

Abstract. Objective: To examine the effect of topically applied tea tree oil (TTO) on histamine-induced oedema in the ears of mice.¶Methods and results: For BALB/c mice, 10 μ undiluted TTO applied immediately after, but not 30 min before intradermal injection of 600 μg histamine in 10 μl, significantly suppressed oedema development. TTO applied after histamine injection also suppressed histamine-induced oedema in C57/BL6 mice. TTO applied immediately after intradermal injection of compound 48/80 (200 μg in 10 μl saline) also significantly reduced ear swelling. TTO suppressed histamine-induced oedema to the same extent in capsaicin-treated (neuropeptide-depleted) and control mice which suggests that TTO does not inhibit histamine-induced oedema by regulating the activity of peripheral sensory neurons. Terpinen-4-ol, the major water-soluble component of TTO, was equivalent in potency to TTO in the suppression of histamine-induced ear swelling.¶Conclusion: Topical application of TTO, and in particular terpinen-4-ol, may be effective in controlling histamine-induced oedema often associated with Type I allergic immediate hypersensitivities.

Monocytes cultured in cytokine-defined environments differ from freshly isolated monocytes in their responses to IL-4 and IL-10.

To investigate the regulatory effects of the prototypic Th2 lymphocyte products and potential immunotherapeutic agents interleukin‐4 (IL‐4) and IL‐10 on macrophages differentiated in vitro under different cytokine‐defined environments, blood monocytes were incubated for 7 days in the presence of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), macrophage colony‐stimulating factor or IL‐4. The effect of monocyte culture in the presence or absence of serum was also investigated. Functional responses by 7‐day‐cultured cells to IL‐4, quantified as decreased CD 14 expression and suppression of lipopolysaccharide (LPS)‐induced tumor necrosis factor‐α (TNF‐α) and IL‐1β production, and as a positive response, increased CD23 expression, were compared directly with the responses by monocytes from which they were derived. In response to IL‐10, decreases in LPS‐induced TNF‐α and IL‐lβ production and reduction in the expression of major histocompatibility complex (MHC) class II antigens were examined. Seven‐day cultured monocytes/macrophages showed (1) diminished TNF‐α production in response to IL‐10 but not EL‐4 (2), diminished IL‐1β production in response to both IL‐4 and IL‐10, and compared with fresh monocytes (3), diminished CD14 expression in response to IL‐4, and (4) a lesser increase in CD23 expression in response to IL‐4. This was the case regardless of the cytokine in the presence of which the cells had been cultured for 7 days. Monocytes cultured for 7 days in GM‐CSF expressed increased levels of MHC class II and LPS‐induced TNF‐α and responded inefficiently to IL‐10 for decreased MHC class II. The responses by monocytes cultured for 7 days with GM‐CSF resemble the published properties of synovial fluid macrophages from patients with chronic inflammatory arthritis. The study highlights the complexity of monocyte/macrophage responses to the immunoregulatory cytokines IL‐4 and IL‐10 and concludes that responses to IL‐4 and IL‐10 by blood monocytes may not be representative of responses by their differentiated or activated counterparts. J. Leukoc. Biol. 57: 909–918; 1995.

Tea tree oil reduces the swelling associated with the efferent phase of a contact hypersensitivity response.

Abstract. Objective: To examine the anti-inflammatory activities of tea tree oil (TTO) in vivo.¶Methods: Mice were sensitized to a chemical hapten, trinitrochlorobenzene, on their ventral skin and 7 days later challenged (or re-exposed) on their dorsal skin with the same hapten.¶Results: TTO applied 30 min before or up to 7 h after to the same dorsal site as hapten challenge caused a significant reduction in skin swelling after 24 h. TTO reduced oedema but not the influx of inflammatory cells. This finding was supported by the inability of TTO to suppress TNFa-induced E-selectin expression by human umbilical vein endothelial cells. TTO did not suppress irritant- or ultraviolet B-induced oedema.¶Conclusion: Topical TTO, specifically the TTO components, terpinen-4-ol and α-terpineol can regulate the oedema associated with the efferent phase of a contact hypersensitivity response.