Alveolar macrophages activated with concanavalin A and peripheral blood monocytes activated with lipopolysaccharide secrete type fi transforming growth factor (TGF-j6). There is minimal TGF-/3 secretion in unactivated monocytes, even though TGF-4 mRNA is expressed in these cells at a level similar to that in activated, lipopolysaccharidetreated cultures. U937 lymphoma cells, which have monocytic characteristics, also express mRNA for TGF-j3. Freshly isolated monocytes, both control and lipopolysaccharide-treated, secrete an acid-labile binding protein that inhibits TGF-,B action. We conclude the following: (i) that expression of TGF-1B mRNA is unrelated to monocyte activation, (ii) that secretion of TGF-fJ is induced by monocyte activation, and (iii) that cosecretion of TGF-13 and its monocyte/macrophage-derived binding protein may modulate growth factor action. In contrast, monocytic expression of other growth factor genes, such as the B chain of platelet-derived growth factor, is not constitutive and requires activation.Type , transforming growth factor (TGF-,l) (1-5), a peptide widely distributed in tissues of humans and other animals, has the unusual ability both to stimulate and inhibit the proliferation of cells in culture (6-10). Although the effect of TGF-,B on epithelial cells is consistently inhibitory (6, 7, 9), its role in mesenchymal cell proliferation is more complex (7,8,11). For example, TGF-,3 acts synergistically with epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) to stimulate mitosis of normal rat kidney (NRK) and smooth muscle cells cultured in soft agar yet antagonizes the effect of these mitogens by inhibiting mitosis of the same cells cultured as subconfluent monolayers (7,8,12,13 3 (8).A second cell type that acts as an important source of growth factors during tissue repair in vivo is the macrophage (18). This cell, which appears in healing wounds prior to the onset of a fibrotic response (19,20), is a paracrine source of growth factors. This paracrine role of macrophages during wound repair in vivo can be demonstrated in studies that show that fibrosis is suppressed when monocyte infiltration is blocked (21). Since activated macrophages are known to secrete PDGF (22-24), the present studies were designed to see if macrophages might also be a paracrine source of TGF-P. Both PDGF and TGF-,3 may have important roles in stimulating smooth muscle cell proliferation in atherogenesis (25) as well as in fibroblastic proliferation in connective tissue repair (13, 16). MATERIALS AND METHODSIsolation and Activation of Human Alveolar Macrophages. Alveolar macrophages were obtained by bronchoalveolar lavage of normal nonsmoking human volunteers; samples typically contained >90% alveolar macrophages, -8% lymphocytes, and <1% polymorphonuclear leukocytes (26). Alveolar macrophages were suspended (106 cells per ml) in serum-free medium [MCDB 104/Dulbecco Vogt phosphatebuffered saline (PBS), 1:1 (vol/vol); Irvine Scientific and GIBCO, respectively] supplemented with bov...

Human macrophages play a key role in atherogenesis and are believed to be the progenitors of the cholesteryl ester (CE)-laden foam cells present in early atherosclerotic lesions. Several mechanisms by which macrophages accumulate CE have been recently described. One involves a perturbation in LDL metabolism subsequent to macrophage activation. Thus, we decided to study the effect of macrophage activation by immune complexes on N-LDL metabolism. Initially, LDL-containing immune complexes (LDL-IC) were chosen, since increased plasma levels of these IC have been reported in patients with coronary heart disease. Human macrophages stimulated for 22 h with LDL-IC (250 micrograms/ml) and incubated afterwards for 20 h with 10 micrograms/ml 125I-N-LDL showed a six- and fourfold increase in the accumulation and degradation, respectively, of 125I-N-LDL over the values observed in nonstimulated cells. Scatchard analysis of 125I-N-LDL-specific binding suggests an increase (20-fold) in the number of LDL receptors in macrophages stimulated with LDL-IC. We studied other immune complexes varying in size and antigen composition. Some of the IC were able to stimulate, although to a lesser degree, the uptake of N-LDL by macrophages. Lipoprotein IC are more efficient and have the greatest capacity to increase N-LDL uptake and CE accumulation. We conclude that human macrophage activation by LDL-IC leads to an increase in LDL receptor activity and promotes in vitro foam cell formation.

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Diabetes mellitus is an independent risk factor in the development of atherosclerosis. In this study we aimed to demonstrate whether there is an abnormal interaction between low-density lipoproteins from diabetic patients and human macrophages. We measured cholesteryl ester synthesis and cholesteryl ester accumulation in human monocyte-derived macrophages (obtained from non-diabetic donors) incubated with low density lipoproteins from Type 1 (insulin-dependent) diabetic patients in good or fair glycaemic control. Low density lipoproteins from the diabetic patients stimulated more cholesteryl ester synthesis than low density lipoproteins from non-diabetic control subjects (7.19 +/- 1.19 vs 6.11 +/- 0.94 nmol/mg cell protein/20 h, mean +/- SEM, p less than 0.05). The stimulation of cholesteryl ester synthesis by low density lipoproteins isolated from diabetic patients was paralleled by a significant increase in intracellular cholesteryl ester accumulation (p less than 0.02). There were no significant differences in the lipid composition of low density lipoproteins between the diabetic and control groups. Non-enzymatic glycosylation of low density lipoproteins was higher in the diabetic group (p less than 0.01) and correlated significantly with cholesteryl ester synthesis (r = 0.58). Similarly, low-density lipoproteins obtained from non-diabetic subjects and glycosylated in vitro stimulated more cholesteryl ester synthesis in macrophages than control low density lipoproteins. The increase in cholesteryl ester synthesis and accumulation by cells exposed to low density lipoproteins from diabetic patients seems to be mediated by an increased uptake of these lipoproteins by macrophages.(ABSTRACT TRUNCATED AT 250 WORDS)

Levamisole has been used in a wide array of clinical research and treatment settings over the past two decades, ranging from such diseases as helminthic infestations to various autoimmune diseases. Numerous preclinical evaluations and clinical trials with levamisole in the cancer arena have been sponsored by the National Cancer Institute and other agencies worldwide with the hopes of demonstrating anticancer activity. Trials in advanced breast cancer, lung cancer, colorectal cancer, melanoma, and lymphoproliferative diseases have generally been negative or inconclusive. However, there is some indication that levamisole may be useful by itself as an adjuvant therapy for resected melanoma; recently it has been shown to be effective in combination with fluorouracil (5-FU) as adjuvant therapy for tumor-node-metastasis (TNM) stage III (Dukes' C) colon carcinoma. In the aggregate, the past 20 years of clinical experience with levamisole has resulted in as many questions as answers. However, further testing of the anticancer activity of levamisole can be expected in clinical research trials over the next few years. Hopefully, these future trials will include studies of the mechanisms of action of this agent.

A total of 11 patients were treated on an escalating, single dose trial of recombinant gamma interferon (rIFN-7), 6 patients by the i.m. and 5 patients by the i.v. route of administration. Dose ranges within each individual were from 0.05 mg/m 2 of IFN (1 mg~> 10 x 106 units of IFN) escalating to 10 mg/m 2. All dosages were delivered twice weekly and the i.v. dose was infused over 5 min. The most common toxicities encountered included fever, chils, fatigue, anorexia, and granulocytopenia. The influenzalike symptoms were very similar to those encountered with IFN-a but were generally less severe. The granulocytopenia was dose-related and transient with recovery generally seen within 48-72 h following administration of rIFN-7. Absolute granulocyte counts only rarely dropped below 1000 mm 3. Hepatotoxicity was not observed. IFN levels were determined by both a bioassay and an enzyme-linked immunosorbent assay. By the i.v. route, the peak level of IFN activity could usually be seen at completion of the infusion with a serum half-life of 30 rain. By the i.m. route, the peak level of serum activity was generally detected between 4-8 h with a serum half-life of 4.5 h after the initial elimination phase. Peak IFN levels appeared to correlate with maximum toxicity. One patient with melanoma had a 25% reduction in a cutaneous lesion, but there were no other minimal, partial, or complete responses.

A B S T R A C T Two human monocyte subsets from the peripheral blood of healthy donors have been isolated in >90% purity by countercurrent centrifugal elutration and human serum albumin gradients and their functional capabilities have been assessed.We have demonstrated that one subset ("regular" monocytes, RM) showed intense cytoplasmic peroxidase staining and contained substantial peroxidase activity. In contrast, another subset ("intermediate" monocytes, IM) stained poorly for peroxidase and had low peroxidase activity. By electron microscopic analysis combined with peroxidase localization, it was found that IM had fewer peroxidase-positive granules per cell than did RM. IM coelutriated with some lymphocytes and by cell sizing analysis were shown to be slightly smaller than RM.Functional and cytochemical analysis of these subsets indicated that IM had less activity than RM in assays such as accessory cell function for mitogen-induced T lymphocyte proliferation and antibody-dependent cellular cytotoxicity, and that fewer IM expressed OKM1 antigen and pokeweed mitogen (PWM) receptors on their membranes than did RM. The subset of IM not bearing either the PWM receptor or the OKM1 antigen had very low peroxidase activity. IM also were found to have a greater sensitivity to polyriboinosinic and polyribocytidilic acid (100 ug/ml)-induced secretion of interferon. There was no significant difference in the phagocytic capability, the percentage Received for publication 21 March 1983 and in revised form 23 May 1983. of Fc receptor-positive cells, 5'-nucleotidase activity, DR antigen expression, or the responsiveness to migration inhibitory factor of IM as compared with RM. Furthermore, it was found that the ratio of IM to RM increased after prolonged cytapheresis, which suggests that IM are more mobilizable than RM from the extravascular reservoirs of human monocytes.