The interleukins, which have a regulatory role in immune function, may also mediate inflammation associated with injury to the brain. In experiments to determine the effect of these peptide hormones on glial cell proliferation in culture, interleukin-1 was a potent mitogen for astroglia but had no effect on oligodendroglia. Interleukin-2 did not alter the growth of either type of glial cell. Activity similar to that of interleukin-1 was detected in brains of adult rats 10 days after the brains had been injured. These findings suggest that interleukin-1, released by inflammatory cells, may promote the formation of scars by astroglia in the damaged mammalian brain.

Abstract. Human hepatoma cells mimic the acute phase response after treatment with monocyteconditioned medium. Levels of secreted fibrinogen, ¢t-1 acid glycoprotein, C-reactive protein, haptoglobin, and the third component of complement were elevated compared with control levels after 48 h of incubation with conditioned supernatant medium from an enriched fraction of normal peripheral monocytes. Albumin levels declined and ~t-1 antitrypsin remained unchanged. Levels of specific mRNA were measured by hybridization to slot blots and Northern blots and changed in correspondence with protein alterations. Interleukin-1 and tumor necrosis factor stimulated the third component of complement, but did not elevate any other member of the acute phase group and were therefore only partially active in this system. The identification of an in vitro model of the human acute phase response will permit analysis of the molecular basis for coordinate regulation of this group of facultative genes.I s response to inflammation and cellular damage, many of the proteins synthesized and secreted by the liver show quantitative changes in serum levels (15,29). These alterations include two-to three-fold elevations of haptoglobin, ct-I antitrypsin (~tlAT), I ct-1 acid glycoprotein (AGP), and fibrinogen. More dramatic increases are seen in C-reactive protein (CRP) and serum amyloid A, which elevate 100-1,000-fold in man. The role that each of these proteins plays in the acute phase response has not been fully defined for all products, but is well reviewed elsewhere (15,22,29). Albumin, in contrast to the other proteins described, decreases in abundance during the response. Several animal models have been used for the analysis of the acute phase response, including rats (2), mice (3, 34), and rabbits (26), each of which has a slightly different subset of proteins that responds to the appropriate stimulation in vivo (e.g., injection of bacteria or turpentine).Whereas animal models have provided much information regarding the kinds of proteins secreted by the liver during the acute phase response and the time course in which they are expressed, in vivo studies are complicated by the multiplicity of cell types in the body and pose some questions about whether the stimulus acts directly or indirectly upon the hepatocyte.Attempting to address these issues, other investigators have used primary hepatocyte cultures (3,31,17). These in L Abbreviations used in this paper: ctlAT, ct-1 antitrypsin; AGE ct-1 acid glycoprotein; C3, third component of complement; CRP, C-reactive protein; hiM, human interleukin-l; I1-1, intedeukin-1; mill, mouse II-1; TNF, tumor necrosis factor. vitro systems have permitted the conclusion that stimulating agents such as turpentine and bacteria do not operate directly on hepatocytes. Rupp and Fuller (32) have shown that one acute phase protein, fibrinogen, was elevated when supernatants derived from isolated peripheral monocytes were added to primary rat hepatocytes in vitro. This demonstration clarified the role of cellul...

The mechanism of the lymphoproliferative effect of the macrophage product lymphocyte-activating factor [LAF(IL1] appears to be mediated by the stimulation of the release of T cell growth factor [TCGF(IL2)] by T cells. The magnitude of the resultant T cell proliferative clonal expansion is thus dependent upon the quantity of both LAF(IL1) and TCGF(IL2) induced by antigen or lectin stimulation. These observations, coupled with the ability to measure the production and actions of these hormone-like lymphokines, should allow for increased insight into the mode of action of immunoenhancing and immunosuppressive agents, as well as for new therapeutic approaches to disease states involving T lymphocytes.

Purified interleukin 2 (IL-2) was found to be sufficient for direct activation of peripheral blood lymphocytes into lymphokine-activated killer (LAK) cells. The LAK activation factor was directly and consistently associated with IL-2 activity using classic protein purification techniques, adsorption to IL-2-dependent cell lines, and inhibition with anti-Tac antibody. As yet, no other cytokines have been found that perform the same role.

Interleukin 1 (IL-1) or lymphocyte-activating factor, a monokine released in vitro by cultured monocytes or macrophages, acts on a variety of somatic and immunerelated target cells in a genetically unrestricted manner (1-5).It has long been recognized that fibroblasts appear at sites of inflammatory reactions after macrophages and play a pivotal role in the repair of damaged connective tissue by synthesizing and remodeling components of the matrix (e.g., collagens, fibronectin, and proteoglycans) (6). In this report, we have observed that IL-1 is a potent stimulator of fibroblast collagenase production in vitro. This finding suggests that ILl may be a major effector molecule by which macrophages modulate not only fibroblast growth but collagenase production as well (4, 5). Materials and Methods IL-1 Purification.In preliminary studies, we found that IL-1 isolated from normal human peripheral blood monocytes was contaminated by lymphokines (personal observation by A. E. Postlethwaite and L. Lachman). However, IL-I from monoblasts from patients with acute monocytic or myelomonocytic leukemia was free of contaminating lyrnphokines and its physicochemical properties were identical to those of IL-1 obtained from normal monocytes (7). IL-1 was purified from supernatants from cultures of monoblasts by diafiltration, uhrafihration, and isoelectric focusing (IEF) as previously described (7,8). The protein content of IL-1 prepared in this manner was below the limit detectable by the Lowry assay (<50 ng/ml).High Performance Liquid Chromatography. Analytical gel filtration high performance liquid chromatography (HPLC) was performed on two 1-125 protein analysis columns (Waters Associates, Inc., Milford, MA) connected in tandem. The columns were equilibrated and run with 0.0075 M glycylglycine:0.14 M NaCI (GGBS) at pH 7.2.Analytical anion exchange-HPLC was also performed on a 250-mm × 4. l-ram SynChropak AX300 column (SynChrom, Inc., Linden, IN). The starting buffer was 0.02 M Tris acetate, pH 8, and the limiting buffer was 0.02 M Tris acetate:0.5 M sodium acetate, pH 8.Thymocyte Proliferation Assay. IL-1 activity was quantitated by measuring the uptake of tritiated thymidine ([3H]TdR) by thymoeytes from 6-to 10-wk-old Swiss-Webster mice (Charles River Breeding Laboratories, Inc., Boston, MA) (7). Standard errors were < 10% of the mean of triplicate determinations,