Effect of IL-1ß and TNF-α vs IL-13 on bronchial hyperresponsiveness, ß2-adrenergic responses and cellularity of bronchial alveolar lavage fluid.

1 Levels of IL-13, IL-1ß and TNF-α are increased in bronchial lavage fluid of asthmatics and induce certain significant features of bronchial asthma including airway hyper-responsiveness (AHR). In this study, we have investigated the effect of these cytokines in naïve mice and those sensitized to ovalbumin (OVA) on bronchoconstrictions to methacholine (MCh) and the functional antagonism induced by ß2 -adrenoceptor agonism. 2 Naïve or OVA-sensitized mice were treated for 3 days with IL-1ß (250 U), TNF-α (150 ng), IL-13 (5 µg) or combinations of IL-1ß with TNF-α or IL-1ß with IL-13. MCh-induced bronchoconstriction and its sensitivity to albuterol, a ß2-adrenoceptor agonist, was assessed 24 h after the last cytokine administration. 3 In naïve mice, responsiveness to MCh was significantly increased by the combination of IL-1ß and TNF-α, IL-13 alone or in combination with IL-1ß, but not by treatment with IL-1ß or TNF-α alone. Similar results were obtained in OVA-sensitized mice except that treatment with IL-13 alone did not increase sensitivity to MCh. 4 In naïve mice, albuterol sensitivity was only significantly attenuated by treatment with IL-1ß and TNF-α in combination. In mice sensitized to OVA, albuterol sensitivity was significantly attenuated by treatment with TNF-α, IL-13 or IL-13 in combination with IL-1ß. 5 Inflammatory cell influx was increased by all cytokines and combinations except IL-13 in OVA-sensitized mice. 6 Our data do not support a link between inflammatory cell influx and AHR. In addition, the mechanism of IL-13-induced AHR might involve decreased ß2-adrenoceptor responsiveness.

The effect of BCG vaccine at birth on the development of atopy or allergic disease in young children.

BACKGROUND: Exposure to infectious diseases may reduce the development of asthma or allergy. In particular, the role of the BCG vaccine in modulating asthma or allergy has been a source of speculation. OBJECTIVE: To study newborns from 3 international sites to evaluate the prospective effect of BCG vaccine on allergic diseases or atopic development. METHODS: Infants were enrolled from newborn and well-infant clinics in Thailand, Argentina, and Turkey. The standard BCG vaccine for each country was given at birth. Parents who consented to have their infant included in the protocol completed an allergy family questionnaire. Infants underwent a standard purified protein derivative (PPD) test at 9 to 12 months of age, and the reaction size was measured. At the age of 2 years, the children returned to be studied. Allergy skin tests to common allergens appropriate to location and age were performed, and the parents completed the International Study of Allergy and Asthma in Childhood questionnaire. The PPD reaction size was compared with the presence of atopy and allergy questionnaire responses. RESULTS: A total of 1,704 infants were studied. Statistical significance was found between a negative PPD response vs any positive PPD response and the risk of having an allergic history at the age of 2 years in Turkey (relative risk, 2.11; 95% confidence interval, 1.25-3.55; P = .005) and Thailand (relative risk, 2.16; 95% confidence interval, 1.18-3.94; P = .02) but not Argentina (relative risk, 1.09; 95% confidence interval, 0.70-1.68; P = .70). CONCLUSIONS: This study further supports the role of infectious agents in modulating asthma and allergy development.

Modification of eosinophil function by suplatast tosilate (IPD), a novel anti-allergic drug.

Suplatast tosilate (IPD), a new dimethylsulfonium agent, is used therapeutically in allergic diseases. Suplatast has been reported to attenuate airway hyperresponsiveness in guinea pigs, human IgE synthesis, and murine peritoneal eosinophilia. However, the effect of suplatast on human eosinophils is not known. In this study, we examined the effects of suplatast in human eosinophils on platelet activating factor (PAF, 1 microM)-induced chemotaxis by the blind well chamber technique, eosinophil adhesion to TNF-alpha (10 ng/ml) or IL-4 (10 ng/ml)-stimulated human umbilical vein endothelial cells (HUVECs), and expression of very late antigen-4 (VLA-4) on eosinophils and vascular cell adhesion molecule-1 (VCAM-1) on HUVECs by flow cytometry. Suplatast suppressed IL-4-induced eosinophil adhesion to HUVECs in a dose-dependent manner. Eosinophils from the normal subjects did not express VLA-4. However, there was a significant increase (P < 0.01) in the basal expression of VLA-4 in allergic patients. PAF or IL-4 did not enhance VLA-4 expression on eosinophils, and there was no significant effect of suplatast on VLA-4 expression in allergic patients. Suplatast did not affect TNF-alpha-induced VCAM-1 expression. Interestingly, suplatast significantly suppressed IL-4 induced VCAM-1 expression on HUVECs and PAF-induced eosinophil chemotaxis. These data suggest that suplatast may modify eosinophil participation in airway inflammation by attenuating inflammatory mediators-induced chemotaxis and adhesion to endothelial cells, and thus might be useful in the treatment of bronchial asthma.

Mycobacterial antigens attenuate late phase response, airway hyperresponsiveness, and bronchoalveolar lavage eosinophilia in a mouse model of bronchial asthma.

Allergens, in combination with genetic predisposition, drive undifferentiated T cells towards the type 2 T cells. Some childhood infections may activate the production of a type 1 T cell profile. It is reasonable to speculate that a decrease in childhood infections may increase the incidence of allergy by allowing the immune balance to shift towards the type 2 T cells. We hypothesized that pre-exposure of mycobacterial antigens in sensitized mice would prevent the development of asthma-like conditions. Specifically, we examined the effect of mycobacterial antigens, Bacillus Calmette-Guerin (BCG) vaccine and Mycobacterium vaccae, on antigen-induced bronchoconstriction, airway hyperresponsiveness to methacholine, bronchoalveolar lavage eosinophilia, and plasma IL-4 and IL-12 levels in ovalbumin (OVA)-sensitized and challenged Balb/c mice. Challenge with OVA produced a 2-3-fold increase in bronchoconstriction within 3-5 min, followed by a delayed response after 60 min, the latter of which was significantly attenuated by both BCG and M. vaccae. Airway hyperresponsiveness to methacholine 24 h after OVA challenge was prevented by BCG and M. vaccae. Airway eosinophilia was also prevented by BCG and M. vaccae. The plasma IL-12 levels were significantly increased and plasma IL-4 levels were significantly decreased following BCG or M. vaccae administration in OVA-sensitized and challenged mice. Interestingly, a significant increase in plasma IL-12 was observed with BCG as compared to M. vaccae administration, suggesting a stronger type 1 response to BCG. These data support our hypothesis and suggest that BCG and M. vaccae may prevent the underlying pathophysiological changes in asthma.

Endogenous nitric oxide in allergic airway disease.

There has been intense research into the role nitric oxide (NO) plays in physiologic and pathologic mechanisms. The presence of NO in exhaled breath and the high concentrations in nasal airways stimulated many studies examining exhaled and nasal NO as potential markers of airway inflammation, enabling repeated monitoring of airway inflammation not possible with invasive tests (eg, bronchoscopy). In airway inflammation, NO is not merely a marker but may have anti-inflammatory and proinflammatory effects. Nasal NO measurement may be used in the noninvasive diagnosis and monitoring of nasal disease. This review was compiled by speakers who gave presentations on NO at the annual meeting of the American Academy of Allergy, Asthma, and Immunology in 1999 on exhaled and nasal NO, in vitro studies of NO, the chemistry of airway NO formation, and standardized measurement of exhaled mediators.

Beclomethasone decreases elevations in phosphodiesterase activity in human T lymphocytes.

BACKGROUND: We recently reported that CD4+ T cells that have been activated in vivo or in vitro contain elevated cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) activity. Since both phosphodiesterase inhibitors and glucocorticoids have anti-inflammatory activity, we sought to investigate the effect of beclomethasone on PDE activity. METHODS: PDE activity was measured in CD4+ T cells after 24 h of culture with beclomethasone. Cells were obtained from the peripheral blood of nonatopic persons (nCells), pre-seasonal (pCells), seasonal (within the first 2 weeks; sCells) and mid-seasonal (mCells) allergic rhinitics and asymptomatic allergic asthmatics (aCells). In addition, the effect of beclomethasone on Th2 cell lines and cells that had been activated in vitro with PHA or interleukin (IL)-2 was determined. RESULTS: PDE activity was decreased in a concentration-dependent manner by incubation of mCells, Th2 lines and PHA or IL-2-activated CD4+ T cells with beclomethasone (p < 0.05). However, beclomethasone did not modulate PDE activity in nCells, pCells, sCells, or aCells. CONCLUSIONS: Beclomethasone only decreases cAMP PDE activity in CD4+ T cells when it is increased by cell activation either in vitro or in vivo.

Therapeutic potential of phosphodiesterase 4 inhibitors in allergic diseases.

Cyclic adenosine monophosphate (cAMP) is thought to be associated with inflammatory cell activity: high levels tend to decrease proliferation and cytokine secretion, whereas low concentrations have the opposite effect (1). Since many phosphodiesterases (PDEs) degrade cAMP, inhibitors of this enzyme decrease inflammatory cell activity. Theophylline, which has nonselective PDE inhibitor activity in addition to its other mechanisms of action, has been used in the treatment of asthma for many years. Unfortunately, because of the important role of PDEs in the cell, nonspecific inhibition of these enzymes causes many undesirable side effects. The discovery of PDE isoenzyme families (PDE1-PDE10), their subtypes (HPDE4 and LPDE4) and their differential distribution among the cell types, as well as their specific functions in controlling cell processes, has led to the development of new, specific PDE4 inhibitors. This review details the rationale for the use of PDE4 inhibitors in the treatment of allergic disease. In addition, the effects of PDE4 inhibitors in vitro, in preclinical animal models and in the clinic are covered. Finally, up-to-date information on the most recently developed inhibitors, such as SB-207499, CDP-840, AWD-12-281 and D-4418, is provided.

Phosphodiesterase type 4 inhibitors, but not glucocorticoids, are more potent in suppression of cytokine secretion by mononuclear cells from atopic than nonatopic donors.

BACKGROUND: Both glucocorticosteroids and phosphodiesterase (PDE) type 4 inhibitors have modulatory effects on PBMC cytokine secretion. In this study we compared the effect of glucocorticoids and PDE inhibitors on IL-10 and TNF-alpha production by PBMCs from nonatopic versus atopic individuals. METHODS: PBMCs were incubated with glucocorticoids (beclomethasone dipropionate and mometasone furoate) or media alone for 24 hours. PDE type 4 inhibitors (Ro20-1724 and rolipram) were then added to the cells preincubated with media. After stimulation with PHA, incubation was continued for 48 hours. The cytokine content of the cell supernatants was determined by ELISA. RESULTS: PDE-4 inhibitors and glucocorticoids caused a concentration-dependent inhibition of the secretion of both TNF-alpha and IL-10. PDE-4 inhibitors were over 20 times more potent in suppressing cytokine secretion by PBMCs from atopic than nonatopic donors, and approximately 5 times more potent in preventing TNF-alpha than IL-10 secretion. In cells from nonatopic donors, glucocorticoids inhibited the production of TNF-alpha to a greater extent than IL-10, but these drugs were more potent in cells from nonatopic than atopic persons. CONCLUSION: In conclusion, both PDE-4 inhibitors and glucocorticoids suppress secretion of TNF-alpha and IL-10. However, because PDE-4 inhibitors are more potent in suppressing cytokine secretion by PBMCs from atopic individuals but less potent in inhibiting production of IL-10, PDE-4 inhibitors may have greater therapeutic potential than glucocorticoids in allergic diseases.

Measurement of bronchoconstriction using whole-body plethysmograph: comparison of freely moving versus restrained guinea pigs.

We have previously measured pulmonary function in guinea pigs using a double-chambered plethysmograph, however, the question remains regarding the accuracy of the double-chamber to gauge the long-term pulmonary function of late asthmatic response. This may be affected by confounding factors, such as stress on the animal and differences in size of the collar around the neck. Therefore, in this study we compared histamine-induced bronchoconstriction in the same guinea pigs using a single- versus a double-chambered body box. In the double-chambered body box, the specific airway resistance is proportional to time delay between thoracic and nasal flows and measured in cmH2O x s. Whereas, in the single-chambered body box, PenH units (Enhanced Pause) reflect "effort of breathing." This is measured as the pause between inspiration and expiration. Doubling concentrations of histamine (12.5-200 microg/ml dissolved in normal saline) were administered by DeVilbiss nebulizer for 1 min, followed by 1 min suction of residual drug in the chamber, and then the airway resistance was recorded by the computer for the following 3 min. There was a 15-min wash-out period between two doses of histamine. There was no statistically significant difference (p > 0.05) in the PC100 values for histamine between the two methods, however, it was much easier to work with the single-chambered body box in terms of handling the animal and eliminating the possible influence of collar placement on the bronchoconstriction. In conclusion, the data suggests histamine challenges produce equivalent PC100 data in both the double-chambered plethysmograph with sRAW units and single-chambered plethysmograph using the PenH units.

Glucocorticoids inhibit proliferation and interleukin-4 and interleukin-5 secretion by aeroallergen-specific T-helper type 2 cell lines.

BACKGROUND: Glucocorticoids play an important role in the treatment of allergic disease. The atopic process, itself, may reduce the response of peripheral blood mononuclear cells (PBMC) to these drugs. OBJECTIVE: In this study we compared the effect of hydrocortisone (HC), beclomethasone (BDP), and mometasone (MF) on interleukin (IL)-4 and IL-5 secretion by aeroallergen-specific T-helper type 2 cells (Th2) and proliferation of PBMC from atopic donors. METHODS: Cells were incubated with drug before stimulating with phytohemagglutinin and assessing proliferation (PBMC) and cytokine secretion (Th2). RESULTS: The glucocorticoids concentration dependently inhibited proliferation and cytokine secretion, but had less effect on proliferation of cells from severe atopics than on cells from those whose symptoms required little treatment. The rank order of potency was MF (average IC50 0.01 nM) > BDP (4.0 nM) > HC (250 nM). CONCLUSIONS: These experiments demonstrate glucocorticoid inhibition of IL-4 and IL-5 secretion by human Th2-like cells and proliferation of PBMC from severely and mildly allergic donors.

Budesonide delivered by Turbuhaler is effective in a dose-dependent fashion when used in the treatment of adult patients with chronic asthma.

BACKGROUND: Airway inflammation is a hallmark of asthma, therefore current treatment recommendations include the use of inhaled glucocorticosteroids (GCS). However, there is little evidence that the effects of inhaled GCS are dose dependent. OBJECTIVES: The objective of this study was to assess the efficacy and safety of a second-generation GCS, budesonide, delivered by Turbuhaler, in adults with chronic asthma. METHODS: In a 12-week, randomized, double-blind, multicenter, parallel-group study, 473 subjects 18 to 70 years of age received either placebo or budesonide (200, 400, 800, or 1600 microg total daily dose) administered twice daily. Primary efficacy end points were mean change from baseline for FEV1 and morning peak expiratory flow. Safety was assessed by reported adverse events and by a cosyntropin-stimulation test. RESULTS: The mean baseline FEV1 was 63% to 66% of predicted normal value between groups. All doses of budesonide were more effective than placebo (p < 0.001). The mean changes in morning peak expiratory flow were 12, 22, 27, and 30 L/min in the 200, 400, 800, and 1600 microg budesonide total daily dose groups, respectively, and -27 L/min for the placebo group. A statistically significant dose-response effect for the mean change from baseline over the 12-week study was seen for both morning peak expiratory flow and FEV1. Budesonide-treated subjects also demonstrated significant reduction in asthma symptoms and bronchodilator use compared with placebo. There were no clinically significant differences in treatment-related adverse experiences among groups. CONCLUSIONS: Budesonide administered by Turbuhaler exhibited a dose response and was effective at low doses. It was well tolerated and significantly more effective than placebo.

The profile of the cytokines secreted during the generation of T-helper cells from atopic asthmatic subjects.

This study investigated cytokine release by T-cell lines from atopic and nonatopic individuals in the presence of specific aeroallergen. Cell lines from atopic and nonatopic individuals secreted IL-2 for less than 14 and more than 21 days, respectively. All of the atopic, but not the nonatopic, cell lines exhibited a biphasic peak in IL-4 and IL-5 secretion. Flow cytometry revealed that, after 35 days, 89.3% of the atopic cells were T helpers and 73.2% were activated. Only 7.4% of the nonatopic cells displayed activation markers. In conclusion, T-cell differentiation may be controlled by other factors in addition to stimulation by aeroallergens.

An in vivo model of beta-adrenoceptor desensitization.

Chronic use of beta2-agonists and increased production of inflammatory mediators during the late allergic reaction after antigen challenge results in the desensitization of beta-adrenoceptors in the airways and the accompanying rise in nonspecific airway hyperresponsiveness. In this study, we established an in vivo model of beta2-adrenoceptor desensitization in guinea pig airways by administration of IL-1beta intratracheally or chronic albuterol by inhalation. In the establishment of beta-adrenoceptor desensitization in response to both beta-agonist or inflammatory mediator, baseline pulmonary function responses were established to methacholine and isoproterenol-induced relaxation of methacholine bronchoconstriction. This was followed by the administration of IL-1beta (500 IU/d intratracheally for 2 days) or chronic albuterol (0.1 g/L by aerosol for 1 min three times a day for 10 days). After administration, the methacholine and isoproterenol-methacholine response was once again evaluated. Intratracheal administration of IL-1beta or chronic administration of albuterol significantly decreased (p < 0.05) the protective effect of isoproterenol on methacholine-induced bronchoconstriction, eliciting beta-adrenoceptor desensitization in vivo. The in vivo model will be very useful in monitoring the effect of other potential drugs on beta-adrenoceptor function in the airways.

Glucocorticosteroids inhibit leukotriene production.

BACKGROUND: The mode of action of corticosteroids, important drugs in the treatment of inflammatory disease, is not yet fully understood. Corticosteroids are known to inhibit phospholipase A2 in unprimed eosinophils and basophils, preventing leukotriene synthesis, but their effect on cells that are already primed is unknown. OBJECTIVE: As inflammatory cells from atopic subjects are often primed in vivo, we studied the effects of two potent corticosteroids on basophil sulfidoleukotriene production in peripheral blood mixed leukocytes (PBML) from in-season and out-of-season atopic individuals. METHODS: Cells were incubated for 24 hours with mometasone furoate or beclomethasone dipropionate, primed with IL-3, stimulated with calcium ionophore, buffer, allergen or anti-IgE, and leukotriene production was quantified. RESULTS: Peripheral blood mononuclear leukocytes from five of ten donors (in season) produced elevated sulfidoleukotrienes without a stimulus; cells from seven donors responded to anti-IgE by increased sulfidoleukotrienes. Neither steroid consistently affected sulfidoleukotriene production in anti-IgE-stimulated cells which were releasing sulfidoleukotrienes in the absence of a stimulant. In comparison, sulfidoleukotriene production was significantly reduced by 0.01 to 10 nM beclomethasone dipropionate or mometasone furoate when the cells were primed with IL-3 after exposure to the drug and stimulated with calcium ionophore or allergen, but no dose-relationship was apparent. Leukotriene production by PBML in response to anti-IgE was potently inhibited by all concentrations of mometasone furoate (0.01 nM to 1 microM) with an inhibitory concentration50 of less than 0.01 nM. Beclomethasone dipropionate inhibited sulfidoleukotriene production in this group (inhibitory concentration50 6 nM) in a dose-dependent manner. CONCLUSIONS: Sulfidoleukotriene production and, conceivably, priming may be more effectively inhibited by mometasone furoate than beclomethasone dipropionate.

Anti-interleukin-4 inhibits immunoglobulin E production in a murine model of atopic asthma.

Immunoglobulin E (IgE) plays an important role in allergy, acting as an initiating factor and being involved in its persistence and exacerbations. As interleukin-4 (IL-4) is critical in IgE synthesis, we propose that treatment of mice with monoclonal anti-IL-4 (11B11) prior to active sensitization with ovalbumin will inhibit IgE synthesis, therefore arresting the allergic process at an early stage. Mice treated with 11B11 and sensitized with saline or ovalbumin had significantly less serum IgE than their respective control groups which were treated with saline (p < 0.05). This study suggests that anti-IL-4 may be a prophylactic agent in asthma and allergic disease.

Human lung mononuclear cells induce nitric oxide synthase in murine airway epithelial cells in vitro: role of TNFalpha and IL-1beta.

Nitric oxide (NO) is a gas released by the airway epithelium, but the mechanism regulating NO release is unclear. We hypothesized that lung mononuclear cell release of tumor necrosis factor alpha (TNF) and interleukin-1beta (IL-1) would induce epithelial cells to release NO. Lung mononuclear cells were obtained from seven normal volunteers by bronchoalveolar lavage and cultured with Escherichia coli lipopolysaccharide for 24 h. The mononuclear cell culture-conditioned media (M-CM) were then applied to cultures of the murine lung epithelial cell line, LA-4. Nitrite and nitrite + nitrate concentrations were 0.9 +/- 0.1 and 11.8 +/- 2.4 microM in the M-CM. Culturing LA-4 cells line with the M-CM (1:10 dilution) resulted in a marked and time-dependent increase in nitrite or nitrite + nitrate compared with LA-4 cells cultured in media alone (2.4 +/- 0.5 versus 0.9 +/- 0.1 microm and 16.6 +/- 0.6 versus 11.8 +/- 2.4 microM after 24 h). Antibodies to TNF and/or IL-1 significantly reduced the nitrite or nitrite + nitrate concentrations and the concentrations of TNF and IL-1 in the M-CM correlated with nitrite concentrations in the LA-4 culture supernatant fluids (r2 = 0.848 and 0.956). Inducible nitric oxide synthase (iNOS) protein and mRNA examined by immunohistochemistry and Northern blot analysis revealed a marked elevation in the cells cultured with the M-CM which was significantly reduced by TNF and IL-1 antibodies. These data demonstrate that mononuclear cells can stimulate LA-4 cells to express iNOS by releasing TNF and IL-1.

Measurement of exhaled nitric oxide by three different techniques.

The purpose of the study was to compare exhaled nitric oxide (NO) determined by three techniques. Ninety-one subjects performed a slow vital capacity maneuver: (1) through the mouth directly into a NO chemiluminescence analyzer (peak oral NO), (2) through the mouth into a collection bag (mean oral NO), and (3) through the nose into a collection bag (mean nasal NO). Peak oral NO was higher in patients with asthma (n = 18, 174.2 +/- 27.0 ppb), but lower in smokers (n = 36, 39.6 +/- 4.8 ppb) compared with nonsmoking control subjects (n = 23, 105.5 +/- 8.4 ppb, p < 0.05 both comparisons). Mean oral NO levels were significantly lower than peak oral NO levels (p < 0.05), but still higher in patients with asthma in comparison with nonsmoking healthy control subjects and asymptomatic smokers (27.2 +/- 3.5 versus 14.5 +/- 1.1 and 7.3 +/- 0.7 ppb, respectively, p < 0.05). In contrast, there was no significant difference in mean nasal NO levels between the three groups. Peak oral NO and mean oral NO levels correlated (r = 0.772, p < 0.0001). Determination of exhaled oral NO levels is qualitatively independent of the technique used, but nasal exhalation may affect NO determination in conditions associated with airway inflammation.

Phosphodiesterase inhibitors suppress proliferation of peripheral blood mononuclear cells and interleukin-4 and -5 secretion by human T-helper type 2 cells.

It has been suggested that interleukin-4 and -5 (IL-4 and IL-5) are instrumental in the control of allergic disease. Elevated levels of IL-4 messenger RNA (mRNA) have been detected in numerous foci of atopic activity, including bronchoalveolar lavage (BAL) fluid from atopic asthmatics and skin of atopic dermatitis patients. IL-5 is important in eosinophil activation, which is a common feature of atopic disease. IL-5 mRNA has been detected in BAL fluid from both atopic and non-atopic asthmatics, indicating that IL-5 may be a common feature of the two disease states. Production of IL-4 and IL-5 by T cells appears to be associated with a high affinity cyclic AMP (cAMP) phosphodiesterase (PDE). This study was designed to compare the effects of PDE inhibitors Ro20-1724 and theophylline on (1) the mitogenic response of peripheral blood mononuclear cells from atopic and non-atopic individuals and (2) secretion of IL-4 and IL-5 by TH(2) cells after activation with PMA and anti-CD3. Both Ro20-1724 and theophylline inhibited proliferation of PBMC in a dose-dependent manner. There was no significant difference between proliferation of PBMC from atopic versus non-atopic donors, but Ro20-1724, a specific PDE IV inhibitor, was more potent at a concentration of 10(-5)M than theophylline in suppressing lymphocyte proliferation. Similarly, both PDE inhibitors suppressed secretion of IL-4 and IL-5 from TH(2)-like cell lines in a dose-dependent manner. In conclusion, as Ro20-1724 and theophylline inhibit proliferation of PBMC and secretion of IL-4 and IL-5 from human TH(2) cell lines, the development of a selective cyclic nucleotide PDE IV inhibitor may provide a promising new approach for asthma prophylaxis.