Pollinosis etiologic relationship between excessive IL-4 production and down-regulation of the...

Previous findings suggest a bi-directional relationship between the immune and endocrine systems, which may expand to a major inflammation-regulatory mechanism, although its mechanism is largely unknown, especially in the human body. Lymphokine and neuroendocrine peptide hormones have been identified as two major groups of immunologic mediators. The particularly pivotal molecules among them are interleukin (IL-1), considered to be a mediator of inflammation, and ACTH, whose activation is induced by IL-1. Among the important functions of lymphokines related to atopic inflammation is the regulation of IgE secretion from B cell through the action of IL-4, produced from the Th2 subset stimulated by IL-1, as a switch factor. IL-4 is the major IgE secretagogue. IL-4 is, moreover, a potent suppressive stimulant of IL-1 secretion. In this study, we tested the hypothesis whether a immunologic interaction exists in patients with allergic rhinitis to Japanese cedar pollen. We performed immunohistochemical staining of IL-1 beta, interleukin 1 receptor (IL-1r) and interleukin-4 (IL-4) in the nasal tissue, and evaluated serum levels of the biochemical mediators involved in the inflammation-regulatory mechanism: IL-1 beta, IL-4, interleukin 1 receptor antagonist (IL-1ra), IgE, cortisol, and ACTH before, during, and after allergen-provoked rhinitis in pollinosis sufferers. Our morphological study showed that, even before the pollen season, large amounts of IL-4 and IL-1r, exclusive of IL-1 beta, were produced in the nasal tissue of patients with seasonal pollinosis. IL-1-positive cells were observed in small amounts in the same tissue, but the quantity was probably enough to cause secretion of intrinsic IL-4 to produce sufficient IgE for atopic inflammation. Upon immunoenzymatic measurement of serum IL-4, even before the pollen season, almost all atopic patients also showed a higher IL-4 level than controls. Serum IgE data also showed a high level before the pollen season in atopic patients. This evidence suggests that atopic patients have already set the first step of inflammatory event not only in the nasal epithelium but also generally even before inhaling proper quantity and quality of the allergen. On the other hand, although atopic patients had inflammation, they did not show an extremely high value of serum IL-1, regarded as inflammatory lymphokine, compared with non-atopic individuals. In contrast, a higher serum level of IL-1ra was observed before and during the pollen season in atopic patients, subsiding to normal level after the season. Serum levels of both cortisol and ACTH did not show a high value in atopic patients during the season. These results demonstrate that excessive IL-4 production of atopic patient causes down-regulated transformation of IL-1 and up-regulated secretion of IL-1ra generally, followed by failure to increase secretion of ACTH from hypophysis and cortisol generally, resulting in defective performance of a specifically useful function of the anti-inflammatory mechanism.