Intranasal challenge with latex allergens induced a strong IgE and eosinophil response with characteristic inflammatory changes in the lungs of mice as reported previously [21,22]. Other features of this model included enhanced IL-4 secretion by antigen stimulated spleen cells and reduced production of IFN-γ. We also detected slightly enhanced mRNA levels of Ly75 (CD-205), MMP-9, and OAT in mice challenged with latex allergens. Immunohistochemistry consistently revealed increased numbers of cells secreting Th2 cytokines in the lungs of mice particularly, IL-4, IL-5, and IL-13. All these features are significant biomarkers detected in allergic subjects and particularly in latex allergy [30]. One of the more striking features was the accumulation of large numbers of inflammatory cells in the perivascular and peribronchiolar regions of the lung parenchyma. The infiltrating cells included lymphocytes, macrophages, and occasional neutrophils with strikingly large numbers of infiltrating eosinophils. Co-stimulatory molecules including CD80, CD86, and OX40L all had increased expression in latex sensitized mice as compared to normal mice [26]. Thus, the model has all the distinguishing features of IgE mediated allergy.
Mice exhibiting allergic responses to latex upon treatment with curcumin showed either reduced expression of several Th2 parameters or they remained unchanged from normal control mice. It is interesting that no major differences were noted in the antibody levels of the latex challenged mice from those sensitized with latex and treated with curcumin. However, total serum IgE was reduced in the latter group of mice. A complete disappearance of eosinophils in the lungs and a consistent reduction in the inflammatory response as indicated by fewer inflammatory loci were two of the more remarkable features in curcumin-treated, latex-sensitized mice. Reduced expression of co-stimulatory molecules on T-lymphocytes, B-lymphocytes, macrophages, and granulocytes was also noted.
Taken together, our data indicate that curcumin is capable of down regulating the allergic response in mice challenged with latex allergens. Although some of the Th2 responses were only marginally reduced in curcumin-treated, latex-sensitized mice, other Th2 parameters were strikingly reduced. The number of IFN-γ expressing cells in the lungs of latex treated mice also increased indicating an admixture of both Th1 and Th2 responses in this model. It is possible that the lung inflammation may be a result of the IFN-γ mediated Th1 response (Fig. 4C, D, E &4F), while the type 1hypersensitivity is the result of a Th2 cytokine and IgE response [24,31,32]. The fewer lesions and less inflammation in the lung of curcumin-treated, latex-sensitized mice support this contention. IFN-γ levels in the lungs of these animals were much lower than those detected in latex challenged and curcumin treated mice where IFN-γ secreting cells were almost comparable to normal control mice treated with curcumin only. This may have profound influence in eliciting the allergic inflammation, a switch from a Th2 cytokine profile in acute lesions to increased IFN-γ levels and high numbers of cytolytic T cells in chronic lesions, while type 2 cytokines still remain high. The results suggest that curcumin reduced the IFN-γ producing cells in the lung resulting in the reduced inflammation that was detected in latex-sensitized mice. Curcumin treatment also reduced various Th2 cytokines producing lung cells.
Ly75 (CD-205), MMP-9, and OAT were all at lower levels in latex-sensitized mice treated with curcumin compared to those not treated with curcumin. Curcumin treated mice also showed reduced expression of TSLP. The reduced TSLP may result in lower IFN-γ production, which then results in a reduced inflammatory lung response [24,33-35]. The reduced TSLP levels further substantiate the reduced inflammatory response induced by curcumin. Arginase metabolism results in the production of ornithine, which produce proline by the activity of the enzyme OAT. Proline inhibits collagen production in the lungs and, therefore, may be directly involved in airway remodeling [36]. Curcumin may have a direct effect on this process by down regulating OAT. In previous reports by us and others, arginase has been shown to be markedly increased in Aspergillus induced allergy [37,38]. Upregulation of enzymes in arginine metabolism may also imply an enhanced nitric oxide (NO) production[36]. MMP-9 correlates with enhanced tissue destruction in allergic airway disease [39], and MMP-9 was markedly increased in latex challenged mice, but showed a reduction in curcumin treated latex sensitized mice. Thus, the inflammatory markers of lung inflammation showed an overall reduction in latex sensitized and curcumin treated mice.
Previous studies have indicated that curcumin reduces inflammation through inhibition of STAT3 phosphorylation [40]. These same findings also indicated that curcumin does not inhibit STAT5 or IFN-γ inducible STAT1 expression. However, curcumin has been shown to inhibit Dermatophagoides farineae induced IL-4 and IL-5 production similar to what we observed in the present study [15]. It has been reported that NO production by Leishmania was decreased in curcumin treated BALB/c mice infected with Leishmania larvae. This reduction in NO is significant as it is a salient feature of asthma and allergy [41].
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