Alveolar Macrophages In Patients Research Articles

CD8 T-Cell Infiltration in Extravascular Tissues of Patients With Human Immunodeficiency Virus Infection. Interleukin-15 Upmodulates Costimulatory Pathways Involved in the Antigen-Presenting Cells–T-Cell Interaction

AbstractInterleukin (IL)-15 regulates the proliferative activity of the CD8+ T-cell pool in human immunodeficiency virus (HIV)-infected patients, thereby contributing to the maintenance of the CD8+ T-cell–mediated immune response against HIV in extravascular tissues, including the lung. However, the effects of IL-15 on antigen-presenting cells (APC) during HIV infection are still unclear. In this study, we evaluated whether IL-15 regulates the macrophage stimulatory pathways governing inflammatory events that take place in the lung of patients with HIV infection. As a first step we evaluated the in vitro effects of IL-15 on lung macrophages retrieved from the respiratory tract of eight normal subjects. Although macrophages from uninfected individuals expressed the IL-15 binding proteins (IL-15Rα and the common γc) at resting conditions, they did not express IL-15 messenger RNA (mRNA). However, a 24-hour stimulation with IL-15 induced the expression of interferon-γ (IFN-γ) and IL-15 itself, suggesting a role for this cytokine in the activation of the pulmonary macrophage pool during inflammation. As a confirmation of the role of IL-15 in this setting, at resting conditions, alveolar macrophages of patients with HIV infection and T-cell alveolitis expressed IL-15, IFN-γ, and IL-15 binding proteins; showed an upmodulation of costimulatory molecules, B7 and CD72, which are involved in the APC of macrophages; and behaved as effective accessory cells because they elicited a strong proliferation of T cells. The accessory effect was inhibited by pretreatment with anti-CD72, anti-B7 (CD80 and CD86), and anti–IL-15 monoclonal antibodies (MoAb). We then investigated the relationship between IL-15 and the expression of costimulatory molecules by macrophages. A 24-hour stimulation of IL-15Rα+/γc+ macrophages with IL-15 upregulated the expression of CD80 and CD86. The evidence that IL-15 upregulates the expression of coligands that favor the contact between T cells and APC, per se, triggers T-cell activation and proliferation and acts as a chemoattractant for T cells, suggests that IL-15 plays a key role in Tc1-mediated defense mechanisms taking place in extravascular tissues of patients with HIV disease.

Immunohistochemical localisation of advanced glycation end products in pulmonary fibrosis.

AIM: To investigate the presence and distribution of advanced glycation end products (AGE) in pulmonary fibrosis. METHODS: Lung tissue samples obtained from seven necropsy cases with idiopathic pulmonary fibrosis and...

659 Production of oxygen free radicals by pulmonary alveolar macrophages in patients with lung cancer

659 Production of oxygen free radicals by pulmonary alveolar macrophages in patients with lung cancer

655 Production of anti-oxidant enzymes by pulmonary Alveolar macrophages in patients with lung cancer

655 Production of anti-oxidant enzymes by pulmonary Alveolar macrophages in patients with lung cancer

Production of tumor necrosis factor alpha and interleukin-6 by alveolar macrophages from patients with rheumatoid arthritis and interstitial pulmonary disease

The aim of this study was to measure the production of tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) by alveolar macrophages in patients with rheumatoid arthritis and interstitial lung disease (ILD). Rheumatoid arthritis patients diagnosed by ACR criteria (n = 8) with associated ILD documented by pulmonary function tests and high resolution computerized tomography scanning, and 12 healthy volunteers (6 smokers and 6 nonsmokers). We determined the spontaneous and induced production of bacterial lipopolysaccharides (LSP), TNF-alpha and IL-6 by alveolar macrophages obtained by bronchoalveolar lavage. The macrophages were isolated by Ficoll-Hypaque gradient centrifugation and plastic adherence and cultured in serum-containing medium (low endotoxin) in the presence and absence of LPS (100 ng/ml). TNF-alpha and IL-6 levels contents were determined in supernatants by ELISA. In the patient group both spontaneous and induced production of TNF-alpha were significantly higher than in controls (p < 0.01). Macrophages stimulated with LPS in patients with rheumatoid arthritis and ILD also released greater amounts of IL-6 than did those of the healthy controls. IL-6 spontaneous and induced production was significantly lower in smokers than in nonsmokers. TNF-alpha and IL-6 production in patients with rheumatoid arthritis and ILD, studied in bronchoalveolar lavage specimens reveals that alveolar macrophages are hyperreactive in these patients, who are possibly sensitized as a consequence of the inflammatory lung process inherent to the disease. Further study is needed to define the pathogenic role of these mediators.

Histochemical Expression of Inducible Nitric Oxide Synthase and Inflammatory Cytokines in Alveolar Macrophages in Patients with ARDS.

To evaluate the role of inducible nitric oxide synthase (iNOS) and proinflammatory cytokines in acute respiratory distress syndrome (ARDS), we immunostained alveolar macrophages (AMs) in the bronchoalveolar lavage fluid (BALF) collected from patients with ARDS, patients in the operating room whose lung function were normal, and non-ARDS patients who were intubated and artificially ventilated for one week in the intensive care unit. We observed the significant expression of iNOS, interleukin-6 (IL-6) and interleukin-8 (IL-8), in AMs obtained from BAL in ARDS patients by the immunocytochemical approach. By comparison, statistically significant elevation was detected in IL-8 levels in BALF supernatant from the ARDS patients compared with the control and the non-ARDS patients. These results suggest that the expression of proinflammatory cytokines and iNOS in AMs as determined by immunocytochemical technique may be an important predictor of the early stage of lung injury in ARDS. We suggest that NO and proinflammatory cytokines produced by AMs might play a pivotal role in acute lung injury. The immunocytochemical approach could be the most sensitive predictor for activated AMs in ARDS patients.

Increased production of hydrogen peroxide and expression of CD11b/CD18 on alveolar macrophages in patients with active pulmonary tuberculosis

Setting: Alveolar macrophages (AM) are important in host defense against Mycobacterium tuberculosis (TB). β2-integrin, especially CD11a/CD18 and CD11b/CD18, are implicated in leukocyte migration, antigen presentation, phagocytosis, and production of reactive oxygen species Objective: To explore the functional relevance of β2-integrin expression to intracellular H 2O 2 capacity of AM in TB patients. Design: In a prospective study, AM retrieved from 18 active pulmonary TB patients and 18 normal subjects were assessed for β2-integrin expression and intracellular H 2O 2 metabolism capacity by loading with anti-CD11a/CD18, anti-CD11b/CD18 monoclonal antibodies and 2′,7′ dichlorofluorescein diacetate (DCFH-DA) respectively, and analyzed by flow cytometry. AM from 8 normal subjects were stimulated with tumor necrosis factor-alpha (TNF-α, 10 5 units/ml) to examine the relationship between H 2O 2 production and CD11b/CD18 expression. Results: The magnitude of DCFH oxidation and CD11b/CD18 expression of AM was higher in TB patients than in normal subjects. The CD11b/CD18 expression was related to the magnitude of DCFH oxidation, but not to lymphocyte numbers or subpopulations (CD4, CD8, CD25). Stimulation of AM with TNF-α increased H 2O 2 production and CD11b/CD18 expression. Pretreatment with CD11b/CD18 monoclonal antibodies inhibited TNF-α-induced H 2O 2. Conclusion: AM in TB patients possessed a higher capacity of oxidant metabolism. The increased CD11b/CD18 expression may be related to the increased respiratory burst response in AM against mycobacterial invasion.

Effects of cytokines on oxygen radical production by peripheral blood monocytes and alveolar macrophages in patients with lung cancer.

The effects of cytokines (interleukin-2, tumor necrosis factor-alpha and interferon-gamma) on the ability of peripheral blood monocytes and alveolar macrophages to produce oxygen radicals were examined by the chemiluminescence assay in patients with lung cancer. Oxygen radical production by peripheral blood monocytes before stimulation with cytokines was lower in the lung cancer group than in healthy controls, suggesting reduced immune function in lung cancer patients. However, the activity in the lung cancer group was elevated to the control level when the monocytes were stimulated by any of the three aforementioned cytokines. Oxygen radical production by alveolar macrophages did not differ significantly between nonstimulated monocytes from lung cancer patients and those from healthy controls. In the lung cancer group, stimulation of the macrophages with any of the three cytokines elevated their ability to produce oxygen radicals to the same extent as in the control group. The results suggest that stimulation of macrophages by interleukin-2, tumor necrosis factor-alpha or interferon-gamma can exert an antitumor action in patients with lung cancer.

Elevated local production of neopterin from alveolar macrophages in patients with internal lung diseases

1. 1. We measured the neopterin level in the supernatant of cultured alveolar macrophages from patients with interstitial lung diseases (ILD patients) as a marker for the activation of alveolar macrophage. 2. 2. In ILD patients, the supernatant neopterin level (40.1±7.8 pmol/ml) was significantly higher ( P<0.01) than that in control subjects (10.0±1.6 pmol/ml). 3. 3. We also found that macrophage-colony stimulating factor (M-CSF) and interleukin-2 (IL-2) augmented neopterin production from alveolar macrophage in both ILD patients (51.6±10.4 and 60.1±10.8 pmol/ml, respectively, P<0.01) and control subjects (28.1±6.0 and 25.7±4.9 pmol/ml, respectively). 4. 4. These findings suggest that alveolar macrophages produce neopterin by M-CSF or IL-2.

Localization of platelet-derived growth factor and insulin-like growth factor I in the fibrotic lung.

To better understand the mechanisms responsible for the increase in numbers of fibroblasts and increased collagen synthesis in fibrotic intestitial lung diseases, platelet-derived growth factor (PDGF)-A and PDGF-B, PDGF receptor-alpha and -beta, insulin-like growth factor I (IGF-I), and IGF-I receptor were evaluated immunohistochemically. Additionally, the messenger ribonucleic acids (mRNAs) for PDGF-A and PDGF-B, PDGF receptor-alpha and -beta, and IGF-I were investigated by in situ hybridization in alveolar macrophages and lung tissues from patients with interstitial lung disease. In specimens of bronchoalveolar lavage fluid (BALF), PDGF-A, PDGF-B, and IGF-I were local in alveolar macrophages in patients with idiopathic pulmonary fibrosis (IPF), patients with sarcoidosis (Sar), and normal individuals. Although there were no differences between IPF and Sar in terms of the staining intensity or number of positive cells, the number of such cells was smaller in the normal controls. In lung tissues with early-stage IPF, PDGF and IGF-I proteins were localized exclusively in alveolar macrophages, mononuclear phagocytes, fibroblasts, alveolar Type II cells, vascular endothelial cells, and vascular smooth-muscle cells. In lung tissues with late-stage IPF and those from normal controls, only alveolar macrophages contained PDGF and IGF-I proteins. Interestingly, the cellular localizations of PDGF receptor-alpha and -beta, and of IGF-I receptor were the same as those of the PDGF and IGF-I proteins in early-stage IPF, whereas these cells were not positive for any of these substances in late-stage IPF or normal controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Interleukin-1 alpha (IL-1 alpha) production by alveolar macrophages in patients with acute lung diseases: the influence of zinc supplementation.

The relationship between zinc treatment and interleukin-1 alpha (IL-1 alpha) production by cultured alveolar macrophages (AM) in patients with pulmonary tuberculosis and bacterial pneumonia was investigated. AM (1 x 10(6) cells/ml) from 6 patients with pulmonary tuberculosis, 7 patients with bacterial pneumonia and 4 healthy volunteers were cultured with either two different concentrations of zinc chloride (Znl = 1 microgram/ml and Zn2 = 5 micrograms/ml) or cell culture media alone (control) for an initial period of 6 hours and then stimulated with 3 different immunomodulator agents and reincubated for a further 24 h. IL-1 alpha in culture supernatants was measured by enzyme-linked immunosorbent assay (ELISA). In the absence of Znl or Zn2 Polyinosinic:Polycytidylic acid (Poly I:C 1 microgram/ml), Lipopolysaccharide (LPS 100 ng/ml) and Tumour necrosis factor-alpha (TNF-alpha 10 ng/ml) significantly increased the production of IL-1 alpha from AM in both patients and healthy subjects (p < 0.001) compared to control (media only). Zn1 and Zn2 significantly increased the production of IL-1 alpha (p < 0.001) in culture supernatants in the absence of either Poly I:C, LPS or TNF-alpha in patients but not in healthy group. In contrast, the presence of LPS or TNF-alpha significantly reduced Zn1 or Zn2-stimulated release of IL-1 alpha from AM in patients and healthy subjects (p < 0.01). However, Poly I:C decreased only Zn1-stimulated release of IL-1 alpha. These results suggest that zinc can regulate the production of IL-1 alpha from AM in patients with pulmonary tuberculosis or bacterial pneumonia.

Alveolar Macrophage Subpopulations in Patients With Active Pulmonary Tuberculosis

Alveolar macrophages are a heterogeneous cell population. The heterogeneity of alveolar macrophages recovered by bronchoalveolar lavage (BAL) from 12 patients with active pulmonary tuberculosis (TB) and 10 normal subjects was studied using Percoll density fractionation. The numbers and subsets (on the basis of CD3, CD4, and CD8 monoclonal antibodies) of lymphocytes in BAL were measured by flow cytometry. Alveolar macrophages recovered from patients with TB were mainly in the lower-density fractions (< 1.030 and 1.030 to 1.040 g/ml), whereas alveolar macrophages from normal subjects were in the higher-density fractions (1.050 to 1.070 and > 1.070 g/ml). There were no significant differences in alveolar macrophages' repartition between smokers and nonsmokers in either patients with TB or normal subjects. The significant changes in the proportions of the lowest fraction and the higher fractions of alveolar macrophages in patients with TB were not altered after division of our patients into smoker and nonsmoker subgroups when compared with corresponding subgroups in normal subjects. The proportion of the alveolar macrophages in the lowest fraction was inversely related to the bacterial load of sputum and the disease extent on chest radiography in TB patients. The CD4/CD8 ratio was significantly higher in patients with TB. This study shows that alveolar macrophages from TB patients are heterogeneous with hypodense cells predominant probably by interaction with T lymphocytes. Changes in the proportions of alveolar macrophages within subpopulations may be of critical importance in determining the overall response of the lung to TB infection.

In Vitro Effect of β2-Agonists on Bacterial Killing and Superoxide Anion (O2−) Release From Alveolar Macrophages of Patients With Chronic Bronchitis

A new class of long-acting beta 2-adrenoceptor agonists has been studied in the last few years. Apparently, they display an important anti-inflammatory activity with an inhibition of different cellular functions. This study was carried out to compare a long-acting beta 2-agonist, formoterol, with a conventional short-acting one, salbutamol, on the release of superoxide anion (O2-) and bacterial killing by alveolar macrophages obtained with bronchoalveolar lavage (BAL) from 20 patients with chronic bronchitis. The O2- production in basal conditions was not affected by beta 2-agonists. On the contrary, after phagocytosis of opsonized zymosan 10(-5) M formoterol significantly affected the phagocytic index (difference between stimulated and basal O2- release): 7.9 +/- 2.0 nM O2-/10(6) AM/10 min vs 16.8 +/- 2.5, p < 0.0007. Bacterial killing was inhibited by the two drugs in a dose-dependent way, but the effect of formoterol was more evident than that of salbutamol. After blocking beta 2-receptors with propranolol, we observed a prevention of the beta 2-agonist effects on both O2- release and bacterial killing. The inhibition of the alveolar macrophage functions considered in this study is evident for both beta 2-agonists, but it is significantly more pronounced for formoterol. Our data can be interpreted as one possible mechanism of the anti-inflammatory effect described for long-acting beta 2-agonists. On the other hand, also a potential suppression of pulmonary antibacterial defenses must not be overlooked, particularly in chronic bronchitis, a disease characterized by recurrent airways infections. Whether current therapeutic dosages are sufficient to achieve anti-inflammatory or microbicidal suppressive effects of clinical relevance has not been demonstrated so far.

Release of interleukin-6 (IL-6) and tumor necrosis factor &alpha; (TNF-&alpha;) from alveolar macrophages in patients with sarcoidosis

Release of interleukin-6 (IL-6) and tumor necrosis factor &alpha; (TNF-&alpha;) from alveolar macrophages in patients with sarcoidosis

Expression of Alveolar Macrophage Adhesion Molecules in Pulmonary Sarcoidosis

Beta-2-integrins belong to a family of leukocyte surface glycoproteins that are essential for immune functions of bronchoalveolar cells. The expression of three alpha chains designed as CD11a, CD11b, CD11c, a common beta chain CD18, and of a ligand for several integrins CD54 (ICAM-1) was studied on alveolar macrophages of patients with active and inactive sarcoidosis and in control subjects. The percentage of macrophages expressing CD11b (CR3) was significantly increased in patients with active sarcoidosis compared with patients who had inactive disease and control subjects. The adhesion molecule CD54 (ICAM-1) was detected on a higher percentage of alveolar macrophages in patients with active rather than inactive sarcoidosis and in control subjects. Since integrin-mediated adhesion seems to be important in macrophage-lymphocyte interactions during the immune response, higher expression of both CD11b and CD54 on sarcoid alveolar macrophages may be related to several immune abnormalities reported in pulmonary sarcoidosis.

Inhibitory Effects of α1 Protease Inhibitor on the Production of IL-1 and TNFα by Alveolar Macrophages in Patients with Lung Cancer

In the present study, we investigated the effect of alpha 1 protease inhibitor (alpha 1PI) on the production of interleukin-1 alpha (IL-1 alpha, ELISA), IL-1 beta (ELISA), and tumor necrosis factor alpha (TNF alpha, ELISA) by alveolar macrophages (AM) recruited by bronchoalveolar lavage (BAL) from patients with lung cancer and benign pulmonary diseases. Levels of BALF alpha 1PI were significantly increased in patients with lung cancer compared with benign pulmonary diseases. When BALF AM were cultured and stimulated by LPS (20 micrograms/ml) for 48 hours, production of IL-1 alpha and IL-1 beta was less marked in patients with lung production showed a similar tendency, but the difference between patients with lung cancer and benign pulmonary diseases was not significant. Addition of alpha 1PI to the LPS-stimulated AM culture system inhibited production of these cytokines dose-dependently. Thus, the local increase of alpha 1PI in lung cancer may act as a humoral inhibitor against the production of IL-1 and TNF by AM.

Increased Numbers of Hypodense Alveolar Macrophages in Patients with Bronchial Asthma

Alveolar macrophages (AM) are among the cells involved in the bronchial inflammation of asthma. It has been shown that AM are a heterogeneous cell population in normal subjects. The heterogeneity of AM from 36 asthmatic patients and 23 normal subjects was studied using Percoll density fractionation. AM recovered from asthmatic patients are mainly in the lower density fractions (1.03 and 1.04 g/ml), whereas AM from normal subjects are in the higher density fractions (1.05 and 1.07 g/ml). Electron microscopic studies showed that low density AM of both asthmatic and normal subjects appear to have morphologic characteristics of activated cells by comparison with high density AM that present characteristics of quiescent cells in both asthmatic and normal subjects. The functional activity of AM fractions of asthmatic and control subjects was assessed using the release of the oxygen free radicals induced by opsonized zymosan and TxB2 generation by A23187. There was no difference between the five fractions of asthmatic or control subjects with regard to oxygen species release. The TxB2 generation was increased in the low density AM from asthmatics when compared with the same fractions of normal subjects. The hypodense cells produced less TxB2 than did cells of higher density in both asthmatic and normal subjects. The density of AM was correlated with the recent instability of the asthma but not with the severity of it. This study shows that AM from asthmatic subjects, when compared with those from control subjects, are heterogeneous, hypodense cells and that they predominate. Hypodense AM did not appear to be hyperresponsive in vitro and may have been already committed into the airways.

Increased Expression of Leukocyte Function Associated Antigen-1 (LFA-1) and Intercellular Adhesion Molecule-1 (ICAM-1) by Alveolar Macrophages of Patients with Pulmonary Sarcoidosis

Leukocyte function associated antigen-1 (LFA-1) and its ligand intercellular adhesion molecule-1 (ICAM-1) are cell adhesion molecules that play an important role in the capacity of monoculear phagocytes (MPs) to present antigens to T lymphocytes. Since in pulmonary sarcoidosis (PS) this capacity is increased at sites of disease activity, we studied the expression of LFA-1 and ICAM-1 on peripheral blood monocytes (BMs) and alveolar macrophages (AM) obtained by bronchoalveolar lavage (BAL) from normal subjects (n = 7) and patients with PS (n = 14). To accomplish this, immunocytochemical stainings were made on cytocentrifuge preparations using anti-LFA-1 (anti-CD 11a) and anti-ICAM-1 (anti-CD 54) monoclonal antibodies (MoAbs). Normal and sarcoid BMs displayed a high percentage of positivity with both MoAbs with no difference between study groups (LFA-1: control BM 87.8 +/- 8.8 percent; sarcoid BM 84.7 +/- 9.5 percent; ICAM-1: control BM 80.8 +/- 10 percent; sarcoid BM 88.0 +/- 4.2 percent; p = NS for all comparisons). In both groups the percentage of cells expressing LFA-1 and ICAM-1 molecules among AMs was lower than among autologous BMs (LFA-1: control AM 46.5 +/- 13.2 percent, p less than 0.001 vs control BM; sarcoid AM 64.2 +/- 15.9; p less than 0.001 vs sarcoid BM) (ICAM-1: control AM 42.7 +/- 8.5 percent, p less than 0.001 vs control BM; sarcoid AM 72.1 +/- 10.6, p less than 0.001 vs sarcoid BM). AMs from patients with PS showed a higher degree of positivity for LFA-1 and ICAM-1 than normal AMs (p less than 0.02 and p less than 0.001, respectively). The positivity for LFA-1 and ICAM-1 molecules on sarcoid AMs was not correlated with the positivity for two different BM-associated markers (ie, the CD 11b and the CD 14 molecules) and was not correlated with the percentage of T lymphocytes in BAL, selected as a marker of the intensity of the alveolitis. These results suggest that the increased ability of sarcoid AMs to induce the proliferation of T lymphocytes may be related, at least in part, to the increased expression of LFA-1 and ICAM-1 molecules on their surfaces.

Impaired tumoricidal function of alveolar macrophages from patients with non-small cell lung cancer.

The capacity of alveolar macrophages and peripheral blood monocytes from patients with non-small cell lung cancer to develop tumoricidal function after in vitro stimulation with different macrophage activators was investigated. Alveolar macrophages were found to be impaired in their ability to develop cytotoxic activity compared with either the peripheral blood monocytes from the same patients or alveolar macrophages from patients with nonmalignant lung disorders. This result was observed consistently under diverse culture conditions and with different macrophage activators including gamma-interferon (gamma-IFN), granulocyte-macrophage colony-stimulating factor (GM-CSF), phorbol myristate acetate, or endotoxin. The impairment in tumoricidal function observed in alveolar macrophages was not associated with reduced target cell binding compared to peripheral blood monocytes. Alveolar macrophages from patients with lung cancer were found to secrete significantly greater amounts of tumor necrosis factor (TNF) and interleukin-1 (IL-1) than either peripheral blood monocytes from the same patients or alveolar macrophages from the patients with nonmalignant disorders. These results are consistent with either different regulatory pathways for cytotoxicity and cytokine secretion in the alveolar macrophages of patients with lung cancer or diversity in the subpopulations of cells responsible for these functions.

IL-1 and IL-1 Inhibitory Activity in the Culture Supernatants of Alveolar Macrophages from Patients with Interstitial Lung Diseases*

Under normal conditions, the release of interleukin 1 (IL-1) and IL-1 inhibitors play a role in tissue homeostasis. We have already reported an increase in IL-1 activity and a decrease in IL-1 inhibitory activity (IHA) in the supernatants of alveolar macrophages from healthy long-term smokers as compared with healthy nonsmokers. In this study, we report an alteration in the release of IL-1 and IL-1 IHA from alveolar macrophages in patients with interstitial lung diseases (sarcoidosis and idiopathic pulmonary fibrosis [IPF]). IL-1 activity released from alveolar macrophages stimulated by lipopolysaccharide was increased in patients with active sarcoidosis (mean +/- SD, 2.52 +/- 1.33 U/ml [n = 6] vs 1.38 +/- 0.62 U/ml [n = 15] for healthy non-current smokers [HNS]; p less than 0.05). IL-1 IHA released from alveolar macrophages was significantly different among the groups examined: a decrease of IL-1 IHA occurred in patients with active sarcoidosis (61.4 +/- 19.2 [n = 6] vs 85.9 +/- 13.9 percent:HNS; p less than 0.05) and IPF (64.7 +/- 18.5 [n = 9]; p less than 0.05). Prednisolone in the culture medium at physiologic concentrations suppressed the release of IL-1 and enhanced the release of IL-1 IHA. IL-1 IHA inhibited not only mouse thymocyte proliferation but also human fibroblast proliferation in the presence of IL-1.