By studying atopic dermatitis, it is possible to select patients with no previous history of asthma or, at least, no previous history of adrenergic medication, so that drug-induced desensitization can be discounted as an explanation for altered β-adrenoceptor responses. In addition, non-selective impairment of mononuclear leucocyte cAMP responses in atopic dermatitis would not be explained either by the presence of a circulating β-adrenoceptor antibody [22] or by a reversal of the α- to β-adrenoceptor ratio on mononuclear leucocytes. Adrenoceptor interconversion with decreased β-adrenoceptor responsiveness linked to increased α-adrenoceptor responsiveness is no longer advocated.
Increased mononuclear leucocyte cAMP phosphodiesterase activity in atopic dermatitis may, in part, be due to in vivo desensitization owing to chronic exposure to circulating histamine and other mediators [23,24]. Mononuclear leucocyte adrenoceptor function will also partly depend on circulating adrenaline (epinephrine) levels, but there is no evidence for desensitization at the level of the adrenal medulla in atopic dermatitis, as adrenaline responses to intravenous histamine infusions are not significantly different from normal responses [25].
Some of the studies on impure mononuclear leucocyte populations have been repeated following isolation of monocytes and lymphocytes, and elevated phosphodiesterase activity has been reported to reside predominantly in the monocyte fraction [26], although Cooper et al. [27], in studies carried out in the same laboratory, also demonstrated elevated phosphodiesterase activity in the lymphocyte fraction. Whether elevated mononuclear leucocyte phosphodiesterase activity in atopic dermatitis is a primary or secondary event is debatable, but elevated levels in the cord blood of neonates from atopic parents [28] does not seem to be a sufficiently specific finding for this biochemical abnormality to be considered a genetic marker for atopy.
However, increased phosphodiesterase activity could underlie defective immune regulation in atopic dermatitis, as increased synthesis of IgE and increased histamine release by atopic leucocytes (presumably basophils) in culture have been shown to correlate with elevated phosphodiesterase activity in the same cells [29,30]. Cooper et al. [29] further demonstrated that a phosphodiesterase inhibitor significantly reduced both the increased cAMP phosphodiesterase activity and the raised spontaneous IgE synthesis in vitro of mononuclear leucocytes from patients with atopic dermatitis. It has been suggested that altered cyclic nucleotide metabolism in T helper lymphocytes in atopic dermatitis could result in abnormalities of T-cell immunoregulation [31]. Alternatively, impaired monocyte control of T-lymphocyte activation might be a consequence of abnormal monocyte cyclic nucleotide metabolism.
There are, in fact, many cyclic AMP-phosphodiesterase isoforms, phosphodiesterase 4 being the predominant enzyme in a variety of inflammatory cells including eosinophils, neutrophils, monocytes and T cells [32]. Intracellular cAMP levels have been shown to regulate house dust mite-induced IL-13 production by T-cells from mite-sensitive patients with atopic dermatitis, this role being blocked in vitro by the phosphodiesterase 4 inhibitor rolipram [33].
The increased production of IgE by B-lymphocytes in atopic dermatitis can be corrected in vitro by exposure of cells to the cAMP phosphodiesterase inhibitor Ro 20-1724 [29]. As discussed above, B-cell IgE synthesis is also regulated by cytokines, increased IL-4 from T-cells in atopic dermatitis being associated with increased synthesis of IgE and decreased production of IFN-γ [34,35]. Evidence for interaction between the cyclic nucleotide cell regulatory system and cytokine-mediated immune dysregulation in atopic dermatitis has been put forward by Chan et al. [36]. Increased IL-4 production was demonstrated in 24-h cultures of mononuclear leucocytes and purified T-cells from patients with atopic dermatitis, there being a strong correlation between phosphodiesterase activity and IL-4 production in the atopic mononuclear leucocyte fraction. IL-4 production in mononuclear leucocytes from patients with atopic dermatitis but not from normal subjects could be reduced by the phosphodiesterase inhibitor Ro 20-1724, this inhibitory effect acting primarily on the monocyte fraction and correlating with increased levels of cAMP. This mechanism, and the apparent increased sensitivity of the phosphodiesterase isoform in atopic dermatitis [36,37], may prove useful in the development of future drug therapy for atopic dermatitis.
Other Cell Regulatory Mechanisms
With regard to the calcium–calmodulin [4,5] and phosphoinositide [6,7] cell regulatory systems, there have been relatively few published studies in atopic dermatitis. The second messengers of the phosphoinositide system, diacylglycerol and inositol 1,4,5-triphosphate, are responsible for the activation of protein kinase C and mobilization of calcium ions respectively. There is some evidence of aberrant protein kinase A and protein kinase C activity in the mononuclear leucocytes of patients with atopic dermatitis [38]. In addition, there is likely to be some degree of interaction between the phosphoinositide and cyclic nucleotide cell regulatory systems. Mallett et al. showed increased mononuclear leucocyte membrane-bound phospholipase C activity in atopic dermatitis compared with healthy controls, suggesting that the phospholipase C enzyme of atopic patients was more sensitive to substrate-driven activity than in non-atopic subjects [39].
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