Vulvar paraneoplastic amyloidosis with the appearance of a vulvar carcinoma.

Nodular cutaneous amyloidosis of the vulva is a rare phenomenon. We describe a patient with localized nodular lesions on the vulva that mimicked kissing ulcers such as are seen with vulvar carcinoma. These lesions were a result of multiple myeloma with subsequent primary systemic amyloidosis. The patient died of cardiac and renal decompensation 2 months after diagnosis.

Effects of stress on alveolar macrophages: a role for the sympathetic nervous system.

Alveolar macrophages (AMs) play an important role in the regulation of the local immune reactivity in the lung. It was previously shown that exposure of rats to mild inescapable electrical footshock stress (20 min, 4 shocks/min, 5 s/shock, 0.8 mAmp) leads to apparent changes in the activity of AMs upon stimulation, reflected by an enhanced interleukin-1beta and tumor necrosis factor-alpha secretion and decreased nitric oxide secretion compared with the secretion by AMs isolated from nonstressed rats. Here we show that in vivo blockade of the autonomic nervous system by intraperitoneal injection of the nicotinic receptor antagonist chlorisondamine leads to complete abrogation of these stress-induced alterations in AM activity. This role for the autonomic nervous system could further be attributed to sympathetic stimulation of beta-adrenergic receptors as shown by blockade of beta-adrenoceptors. Blockade of either alpha-adrenoceptors or parasympathetic output did not result in abrogation of the stress-induced changes in AM activity. The beta-adrenergic modulation of AM activity most likely is not due to a direct effect of catecholamines on AMs because mimicking the in vivo stress effects by in vitro preincubation of AMs with various doses of catecholamines followed by lipopolysaccharide stimulation did not result in an altered cytokine secretion by AMs.

Acute and long-term effects of stressors on pulmonary immune functions.

To study the effects of different types or intensities of stressors on immune reactivity in the lungs, we studied the ex vivo production of nitric oxide (NO) and IL-1beta by alveolar macrophages (AM) after short exposure of rats to restraint stress or inescapable electric footshocks. Exposure to electric footshocks of various intensities resulted in an intensity-dependent decrease in NO production whereas the IL-1beta production by AM had increased. The secretory activity was similarly affected by restraint stress. When the time course of electric footshocks on secretory functions of AM was studied, it was found that the effects on NO and IL-1beta production by AM were normalized 3 days after the stress induction, but reappeared when cells were isolated 1 to 2 wk after stress exposure. Analysis of the effects of electric footshocks of various intensities on antibody production 10 days after the stress session and subsequent lung immunization with trinitrophenyl conjugated keyhole limpet hemocyanin (TNP-KLH), showed a footshock intensity-dependent response. Although exposure to stress induced an increase in plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone (CORT), hormone levels did not differ between the various stress-exposed groups. This suggests that the observed stress effects on pulmonary immune functions were not mediated by ACTH or CORT but point to a direct involvement of the autonomic nervous system.

Gradual inhibition of inducible nitric oxide synthase but not of interleukin-1 beta production in rat microglial cells of endotoxin-treated mixed glial cell cultures.

In cultures of purified microglial cells and astrocytes from newborn rats, the immunocytochemical localization of interleukin-1 beta (IL-1 beta) and inducible nitric oxide synthase (iNOS) using recently developed antibodies, as well as the release of IL-1 beta and nitric oxide (NO), was studied following exposure of the cells to endotoxin [lipopolysaccharide (LPS)]. In the absence of LPS, IL-1 beta- and iNOS-immunoreactive microglial cells and IL-1 beta or NO release were not observed, whereas in the presence of the endotoxin, the production of NO and IL-1 beta by microglial cells dramatically exceeded their synthesis and release by astrocytes. Interestingly, microglial cells cultured for 4-8 days in the presence of astrocytes appeared to lose their ability to produce iNOS, whereas the release of IL-1 beta remained unaltered. Moreover, endotoxin-stimulated microglial cells appeared to regain their ability to synthesize iNOS following their separation from astrocytes. These data show that microglia are primarily responsible for NO and IL-1 beta production in mixed glial cell cultures upon endotoxin stimulation. Moreover, in the presence of astrocytes the induction of iNOS, but not that of IL-1 beta in microglial cells is gradually inhibited.

Alveolar macrophages autoregulate IL-1 and IL-6 production by endogenous nitric oxide.

The effect of nitric oxide on the lipopolysaccharide (LPS)-induced cytokine production by alveolar macrophages was studied. When alveolar macrophages were cultured, substantial amounts of interleukin-1(IL-1), interleukin-6 (IL-6), tumor necrosis factor alpha(TNF-alpha), and nitric oxide are produced upon stimulation with LPS. Inhibition of the nitric oxide production by the L-arginine analogue N(G)-monomethyl-L-arginine (NMMA), resulted in an increase of IL-1(beta) and IL-6, whereas the TNF-alpha concentrations remained unchanged, suggesting specific inhibitory effects of nitric oxide on the LPS-stimulated cytokine production by alveolar macrophages. The observed cytokine-modulation properties of nitric oxide did not result from cytotoxic actions of the oxidation of L-arginine on macrophages, since nitric oxide synthesis did not affect the viability of the alveolar macrophages. Conversely the nitric oxide donor S-nitroso-N-acetyl-D, L-penicillamine (SNAP) induced dose-dependent inhibition of IL-1 production in LPS-stimulated alveolar macrophages in which endogenous nitric oxide production was blocked. The results indicate that nitric oxide can affect the LPS-induced IL-1beta and IL-6 secretion by alveolar macrophages in an autoregulatory way and are discussed in view of the important physiologic consequences this autoregulation by nitric acid oxide may have.

Acute stress affects cytokines and nitric oxide production by alveolar macrophages differently.

The production of cytokines by alveolar macrophages was studied after exposure of rats to an acute stress paradigm (mild inescapable footshocks). When alveolar macrophages from nonstressed animals were isolated and cultured, they readily produced interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) after stimulation with lipopolysaccharides (LPS). For these cytokines the dose response relationship for LPS was clearly biphasic. Nitric oxide (NO) production could only be detected upon LPS stimulation and seemed to be monophasic. However, when the animals were exposed to the acute stress paradigm, isolated alveolar macrophages (AM) showed a marked increase of IL-1 beta and TNF-alpha secretion upon LPS stimulation in vitro, but no changes in the production of IL-6 were detected. In contrast, exposure to the stress paradigm resulted in a strong decrease in NO production. The results indicate that emotional stress can rapidly induce altered behavior of AM, which is discussed in view of the important role these cells play in the regulation of the local immune responses in the lungs and the possible contribution to asthma.

Changes in cytokine and nitric oxide secretion by rat alveolar macrophages after oral administration of bacterial extracts.

Oral administration of the bacterial immunomodulator Broncho-Vaxom (OM-85), a lysate of eight bacteria strains commonly causing respiratory disease, has been shown to enhance the host defence of the respiratory tract. In this study we examined the effect of orally administered (in vivo) OM-85 on stimulus-induced cytokine and nitric oxide secretion by rat alveolar macrophages in vitro. The results show that alveolar macrophages isolated from OM-85-treated rats secreted significantly more nitric oxide, tumour necrosis factor-alpha (TNF-alpha) and IL-1 beta upon in vitro stimulation with lipopolysaccharide (LPS), whereas, in contrast, LPS-induced IL-6 secretion was significantly lower. The observed effects of in vivo OM-85 treatment on stimulus-induced cytokine secretion in vitro are not due to a direct effect of OM-85 on the cells, because in vitro incubation of alveolar macrophages with OM-85 did not result in altered activity, nor did direct intratracheal instillation of OM-85 in the lungs of rats result in altered alveolar macrophage activity in vitro. It is hypothesized that oral administration of OM-85 leads to priming of alveolar macrophages in such a way that immune responses are non-specifically enhanced upon stimulation. The therapeutic action of OM-85 may therefore result from an enhanced clearance of infectious bacteria from the respiratory tract due to increased alveolar macrophage activity.

Increased specific IgE production in lungs after the induction of acute stress in rats.

Under normal conditions, immune responses in the lung are suppressed, resulting in low antigen-specific serum antibody titers after intratracheal immunization of rodents. We attempted to determine whether mild inescapable electric foot-shock stress, immediately followed by intratracheal instillation of trinitrophenyl-conjugated keyhole limpet hemocyanin, could enhance the primary and secondary humoral immune responses in male Wistar rats. This acute emotional stress paradigm and subsequent intratracheal administration of trinitrophenyl-conjugated keyhole limpet hemocyanin resulted in a dramatic increment of trinitrophenyl-specific immunoglobulin isotype concentrations in serum, including IgE. Analysis of paratracheal lymph node and spleen tissue for trinitrophenyl-specific antibody-forming cells revealed that the increased specific antibody concentrations resulted from a local production in the paratracheal lymph nodes. Because the presence of aeroantigen-specific IgE is associated with diseases such as allergic asthma, we advocate the view that acute emotional stress can contribute to the onset or severity of allergic asthma by lowering the threshold of induction of aeroantigen-specific IgE production in the lungs.

Activation of the hypothalamus-pituitary-adrenal axis by bacterial endotoxins: routes and intermediate signals.

Peripheral administration of endotoxin induces brain-mediated responses, including activation of the hypothalamus-pituitary-adrenal (HPA) axis and changes in thermoregulation. This paper reviews the mechanisms by which endotoxin affects these responses. The effects on thermoregulation are complex and include macrophage-dependent hyperthermic and hypothermic responses. Low doses of endotoxin, given IP, activate peripheral macrophages to produce interleukin (IL)-1 beta, which enters the circulation and acts as a hormonal signal. IL-1 may pass fenestrated endothelium in the median eminence to stimulate corticotropin-releasing hormone (CRH) secretion from the CRH nerve-terminals. In addition, IL-1 may activate brain endothelial cells to produce IL-1, IL-6, prostaglandins, etc., and secrete these substances into the brain. By paracrine actions, these substances may affect neurons (e.g., CRH neurons) or act on microglial cells, which show IL-1-induced IL-1 production and therefore amplify and prolong the intracerebral IL-1 signal. In contrast, high doses of endotoxin given i.v. may directly stimulate endothelial cells to produce IL-1, IL-6, and prostaglandin-E2 (PGE2) and thereby activate the HPA axis in a macrophage-independent manner.