John J. Finlay-Jones

Modulation of the immune system by UV radiation: more than just the effects of vitamin D?

Humans obtain most of their vitamin D through the exposure of skin to sunlight. The immunoregulatory properties of vitamin D have been demonstrated in studies showing that vitamin D deficiency is associated with poor immune function and increased disease susceptibility. The benefits of moderate ultraviolet (UV) radiation exposure and the positive latitude gradients observed for some immune-mediated diseases may therefore reflect the activities of UV-induced vitamin D. Alternatively, other mediators that are induced by UV radiation may be more important for UV-mediated immunomodulation. Here, we compare and contrast the effects of UV radiation and vitamin D on immune function in immunopathological diseases, such as psoriasis, multiple sclerosis and asthma, and during infection.

Terpinen-4-ol, the main component of the essential oil of Melaleuca alternifolia (tea tree oil), suppresses inflammatory mediator production by activated human monocytes

Abstract:Objective and Design: To evaluate potential anti-inflammatory properties of tea tree oil, the essential oil steam distilled from the Australian native plant, Melaleuca alternifolia.¶Material and Methods: The ability of tea tree oil to reduce the production in vitro of tumour necrosis factor-α (TNFα), interleukin (IL)-1β, IL-8, IL-10 and prostaglandin E2 (PGE2) by lipopolysaccharide (LPS)-activated human peripheral blood monocytes was examined.¶Results: Tea tree oil emulsified by sonication in a glass tube into culture medium containing 10% fetal calf serum (FCS) was toxic for monocytes at a concentration of 0.016% v/v. However, the water soluble components of tea tree oil at concentrations equivalent to 0.125% significantly suppressed LPS-induced production of TNFα, IL-1β and IL-10 (by approximately 50%) and PGE2 (by approximately 30%) after 40 h. Gas chromatography/ mass spectrometry identified terpinen-4-ol (42%), α-terpineol (3%) and 1,8-cineole (2%, respectively, of tea tree oil) as the water soluble components of tea tree oil. When these components were examined individually, only terpinen-4-ol suppressed the production after 40 h of TNFα, IL-1β, IL-8, IL-10 and PGE2 by LPS-activated monocytes. Conclusion: The water-soluble components of tea tree oil can suppress pro-inflammatory mediator production by activated human monocytes.

Topically applied 1,25-dihydroxyvitamin D3 enhances the suppressive activity of CD4+CD25+ cells in the draining lymph nodes.

The immunomodulatory effects of vitamin D have been described following chronic oral administration to mice or supplementation of cell cultures with 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active form of vitamin D. In this study, topically applied 1,25(OH)2D3, enhanced the suppressive capacity of CD4+CD25+ cells from the draining lymph nodes. The effects of topical 1,25(OH)2D3 were compared with those of UVB irradiation, which is the environmental factor required for 1,25(OH)2D3 production in skin. CD4+ cells from the skin-draining lymph nodes (SDLN) of either 1,25(OH)2D3-treated or UVB-irradiated mice had reduced capacity to proliferate to Ags presented in vitro, and could suppress Ag-specific immune responses upon adoptive transfer into naive mice. This regulation was lost upon removal of CD4+CD25+ cells. Furthermore, purified CD4+CD25+ cells from the SDLN of 1,25(OH)2D3-treated or UVB-irradiated mice compared with equal numbers of CD4+CD25+ cells from control mice had increased capacity to suppress immune responses in both in vitro and in vivo assay systems. Following the sensitization of recipient mice with OVA, the proportion of CD4+Foxp3+ cells of donor origin significantly increased in recipients of CD4+CD25+ cells from the SDLN of 1,25(OH)2D3-treated mice, indicating that these regulatory T cells can expand in vivo with antigenic stimulation. These studies suggest that 1,25(OH)2D3 may be an important mediator by which UVB-irradiation exerts some of its immunomodulatory effects.

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.