Interleukin-1β up-regulates tumor necrosis factor receptors in the mouse airways (original) (raw)
Related papers
Regulation of interleukin-1 and interleukin-1 inhibitor release by human airway epithelial cells
European Respiratory Journal, 2004
In asthma, human airway epithelial cells (HAECs) regulate the intensity of mucosal inflammation, in part, by releasing the pro-inflammatory cytokine interleukin (IL)-1b. However, the IL-1b inhibitors, IL-1 receptor antagonist (IL-1RA) and soluble IL-1 receptor type II (sIL-1RII), regulate IL-1b bioactivity. In order to better understand the control of IL-1b activity in the airway mucosa, the role(s) of tumour necrosis factor (TNF)-a, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) in the release of IL-1b and its inhibitors by cultured HAECs were examined. HAECs were treated with TNF-a (2-200 ng?mL-1), dibutyryl cAMP (0.01-1 mM), 8-bromo-cGMP (0.01-1 mM) or vehicle for 24 h, and cytokine levels in the HAECconditioned medium were measured by enzyme-linked immunosorbent assay. HAECs produced IL-1b, IL-1RA and sIL-1RII constitutively, but the inhibitor concentrations greatly exceeded that of IL-1b (by y100and y550-fold, respectively). TNF-a dose-dependently increased the levels of all IL-1b cytokine family members. However, over the range of TNF-a concentrations studied, IL-1b concentration increased more than those of its inhibitors. cAMP increased constitutive and TNF-astimulated IL-1b release but reduced that of sIL-1RII. In contrast, cGMP had no effect on IL-1b but reduced IL-1RA and sIL-1RII release. Under basal conditions, the disproportionate release of inhibitors relative to interleukin-1b by human airway epithelial cells probably prevents interleukin-1bmediated biological effects. Tumour necrosis factor-a, cyclic adenosine monophosphate and cyclic guanosine monophosphate may potentiate mucosal inflammation by increasing interleukin-1b levels relative to those of its inhibitors in the airway mucosa.
American Journal of Respiratory and Critical Care Medicine, 1996
Accumulating evidence suggests that the cytokine network is central to the immunopathology of bronchial asthma and recent findings have suggested that naturally occurring cytokine antagonists may also be involved. In this study we looked atthe expression of interleukin-1 beta (ll-1 P) and its naturally occurring receptor antagonist, Il-1 ra, in the normal and asthmatic bronchial wall. Frozen bronchial biopsies from 12 normal and 18 asthmatic individuals were double stained with EBM11 (a CD68 macrophage marker) and either a rabbit anti-ll-1 por a rabbit anti-ll-1 ra. Hue-saturation-intensity color image analysis (HSI) was used to quantify the brown immunoperoxidase reaction product present on the bronchial epithelium. There was an increased expression of both Il-1 pand Il-1 ra in the asthmatic bronchial epithelium, p < 0.0002 and p < 0.0001, respectively. Additionally, the numbers of macrophages, of Il-1 Pproducing cells, and the percentage of macrophages producing Il-1 Pwere significantly increased in the asthmatic submucosa (p <0.004, P <0.002, and p <0.008, respectively). Sousa AR, Lane SJ, Nakhosteen JA, Lee TH, Poston RN. Expression of Interleukln-l beta (IL-l P) and Interleukln-l receptor antagonist (IL-l ra) on asthmatic bronchial epithelium.
Role and regulation of interleukin-1 molecules in pro-asthmatic sensitised airway smooth muscle
European Respiratory Journal, 2004
Interleukin (IL)-1b is a pleiotropic, pro-inflammatory cytokine that has been importantly implicated in driving the inflammatory response and resultant changes in airway smooth muscle (ASM) responsiveness in asthma. IL-1b belongs to a family of molecules, known as the IL-1 axis, which exert both pro-and anti-inflammatory effects. Since dysregulation of IL-1 axis molecules may be critical in the pathobiology of asthma, the present study examined the expression and activation of both the inhibitory and stimulatory IL-1 axis molecules in human ASM cells and their roles in modulating cytokine and immunoglobulin (Ig)E immune complex (IgE cx)-mediated changes in rabbit ASM constrictor and relaxant responsiveness. The results demonstrate the following. 1) Pre-treatment of isolated rabbit tracheal rings with the inhibitory IL-1 axis members, IL-1 receptor antagonist and IL-1 type-II receptor abrogated both IL-5-and IgE cx-induced changes in ASM responsiveness. 2) Administration of IL-5, IL-1b and IgE cxs to human ASM cells increased mRNA and protein expressions of both stimulatory and inhibitory IL-1 axis molecules. 3) The time course of IL-5-induced IL-1 axis molecule expression preceded that of both IL-1b and IgE immune cxs. Collectively, these findings suggest that modulation at the level of the interleukin-1 axis of molecules may have significant therapeutic potential in the treatment of asthma.
1997
The role of IL-1  in regulating altered airway responsiveness in the atopic/asthmatic sensitized state was examined in isolated rabbit tracheal smooth muscle (TSM) tissue and cultured cells passively sensitized with sera from atopic asthmatic patients or nonatopic/nonasthmatic (control) subjects. During half-maximal isometric contraction of the tissues with acetylcholine, relative to control TSM, the atopic sensitized TSM exhibited significant attenuation of both their maximal relaxation (P Ͻ 0.001) and sensitivity (i.e., Ϫ log dose producing 50% maximal relaxation) to isoproterenol and PGE 2 (P Ͻ 0.05), whereas the relaxation responses to direct stimulation of adenylate cyclase with forskolin were similar in both tissue groups. The impaired relaxation responses to isoproterenol and PGE 2 were ablated in sensitized TSM that were pretreated with either the IL-1 recombinant human receptor antagonist or an IL-1 neutralizing antibody. Moreover, extended studies demonstrated that, in contrast to their respective controls, both passively sensitized rabbit TSM tissue and cultured cells exhibited markedly induced expression of IL-1  mRNA at 6 h after exposure to the sensitizing serum, a finding similar to that also obtained in passively sensitized human bronchial smooth muscle tissue. Finally, unlike their respective controls, passively sensitized TSM tissue and cultured cells also displayed progressively enhanced release of IL-1  protein into the culture media for up to 24 h after exposure to atopic/asthmatic serum. Collectively, these observations provide new evidence demonstrating that the altered responsiveness of atopic/asthmatic sensitized airway smooth muscle is largely attributed to its autologously induced expression and autocrine action of IL-1 . (
IL-1β Augments TNF-α–Mediated Inflammatory Responses from Lung Epithelial Cells
Journal of Interferon & Cytokine Research, 2009
Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) mediate the development of numerous infl ammatory lung diseases. Since IL-1β is typically activated in situations where TNF-α is produced, it was hypothesized that IL-1β alters TNF-α-induced proinfl ammatory epithelial cell function by altering TNF receptor shedding and surface abundance. In this study, the impact of IL-1β on TNF-α-mediated chemokine production as well as TNF receptor surface expression and shedding were investigated from mouse pulmonary epithelial cells (MLE-15). Interleukin-1β rapidly and persistently enhanced soluble and surface TNFR2. These effects were dependent on TNFR1 expression. TNFR2 small-interfering RNA (siRNA) shifted IL-1β responses, signifi cantly increasing surface and shed TNFR1 implying IL-1β selectively modifi es TNF receptors depending on cellular receptor composition. mRNA expression of both receptors was unaltered by IL-1β up to 24 h or in combination with TNF-α indicating effects were post-transcriptional. Interleukin-1β pretreatment enhanced TNF-α-induced macrophage infl ammatory protein (MIP)-2 and KC mRNA expression as well as MIP-2 and KC protein levels at the same time point analyzed. Experiments utilizing siRNA against the TNF receptors and a TNFR1 neutralizing antibody demonstrated TNF-α induced MIP-2 through TNFR1, whereas both receptors may have contributed to KC production. These data suggest IL-1β modulates TNF-α-mediated infl ammatory lung diseases by enhancing epithelial cell TNF receptor surface expression.
Mediators of Inflammation, 2009
We determined the role of interleukin-1β (IL-1β) signaling on tumor necrosis factor alpha-induced (TNF-α) lung neutrophil influx as well as neutrophil chemoattractant macrophage inflammatory protein (MIP-2) and KC and soluble TNF-α receptor (TNFR) levels utilizing wildtype (WT), TNF receptor double knockout (TNFR1/TNFR2 KO), and IL-1β KO mice after oropharyngeal instillation with TNF-α. A significant increase in neutrophil accumulation in bronchoalveolar lavage fluid (BALF) and lung interstitium was detected in the WT mice six hours after TNF-α exposure. This correlated with an increase in BALF MIP-2. In contrast, BALF neutrophil numbers were not increased by TNF-α treatment of IL-1β KOs, correlating with a failure to induce BALF MIP-2 and a trend toward increased BALF soluble TNFR1. TNF-α-instillation increased lavage and serum KC and soluble TNFR2 irrespective of IL-1β expression. These results suggest IL-1β contributes, in part, to TNF-α-mediated, chemokine release, and neutrophil recruitment to the lung, potentially associated with altered soluble TNFR1 release into the BALF.
American Journal of Respiratory Cell and Molecular Biology, 2000
Airway smooth muscle (ASM) is considered to be an end-target cell for the effects of mediators released during airway wall inflammation. Several reports suggest that activated ASM may be capable of generating various proinflammatory cytokines. We investigated the effects of tumor necrosis factor (TNF)-␣ , a potent proinflammatory cytokine, on cultured human ASM cells by examining the expression and release of the cytokine interleukin (IL)-6, cell proliferation, and the expression pattern of c-fos and c-jun , two nuclear proto-oncogenes constituting the activator protein-1 transcription factor. Growth-arrested cell monolayers were stimulated with human recombinant TNF-␣ in a concentration-and time-dependent manner. TNF-␣ stimulated the expression of IL-6 messenger RNA (mRNA), which was detected after 15 min, reaching a maximum at 1 h. IL-6 protein was readily detected in ASM cell-conditioned medium after 2 h of TNF-␣ stimulation. Protein levels increased in a time-and concentration-dependent manner. Release of IL-6 elicited by TNF-␣ was significantly inhibited by dexamethasone, cycloheximide, and nordihydroguaiaretic acid (NDGA). TNF-␣ did not alter DNA biosynthesis up to 48 h or cell numbers up to 120 h. Northern blot analysis of proto-oncogene expression revealed that c-fos and c-jun mRNA levels were elevated after 30 min of TNF-␣ incubation with maximum levels at 1 h and 45 min, respectively. Expression of c-fos mRNA was downregulated by NDGA. Four hours of TNF-␣ treatment resulted in translocation of c-jun immunofluorescence from the cytoplasm to the nucleus in human ASM cells. Our results suggest that despite the lack of a mitogenic response to TNF-␣ , upregulation of primary response genes in human ASM cells may account for the induction of proinflammatory cytokines, such as IL-6, in human airways.