Antiretroviral therapy administered during primary HIV infection may improve the subsequent clinical course and increase the CD4 cell count.

To study the interaction of lymphocytes and macrophages in the control of extracellular matrix turnover, we determined the effects ofseveral soluble T cell products on mononuclear phagocyte production of metalloproteinases. Cytokines including IL-2, IL4, IL-6, tumor necrosis factor a (TNFa), GM-CSF, and IFN-gamma were each tested for capacity to modulate macrophage metalloproteinase and tissue inhibitor of metalloproteinases (TIMP) expression. The addition of IL4 to cells cultured under basal conditions caused a dose-dependent suppression in the release of 92-kD type IV collagenase without affecting TIMP production. 92-kD enzyme secretion was inhibited by 50% with 1-2 ng/ ml of IL4 and by 90% with 10 ng/ml of IL4. When cells were first exposed to killed Staphylococcus aureus to induce metalloproteinase production, IL4 potently blocked the stimulated release of both interstitial collagenase and 92-kD type IV collagenase, again without effect upon TIMP. Metabolic labeling experiments and Northern hybridizations demonstrated that IL4 exerted its action at a pretranslational level. Furthermore, IL4 possessed the capacity to inhibit metalloproteinase expression even in the relatively immature peripheral blood monocyte. As reported previously

Unlike agonists such as cytokines or hormones, the biological activity of bacterial lipopolysaccharide (LPS) is substantially modified by serum proteins. One such interaction in serum is with high-density lipoprotein (HDL) forming LPS-HDL complexes. LPS-HDL complexes have been previously shown to have reduced endotoxic activity, for example pyrogenicity, when compared to other forms of LPS in animal models. In this study, we report results of studies comparing the potency of LPS-HDL cmplexes with uncomplexed LPS as agonists for interleukin-1 (IL-1) production by two different sources of monocytes. LPS-HDL complexes were purified by ultracentrifugation in sodium bromide gradients. The human monocytic cell line THP-1 and the freshly isolated human monocytes, purified by adherence or elutriation from venous blood from healthy donors, were exposed to medium alone containing 1 mg/ml bovine serum albumin, HDL, LPS (parent LPS) and LPS-HDL complexes. mRNA level was analyzed on Northern blot, and cell-associated protein and supernatants were tested for IL-1 production using immunologic and biologic assays. LPS stimulates substantially more IL-1 mRNA and cell-associated IL-1 protein when the monocytes are stimulated with LPS alone versus LPS-HDL. These data suggest that LPS-HDL complexation may contribute to a reduction in endotoxic activities in vivo by preventing LPS (lipid A) from generating important transmembrane signals after binding to cells.

Human alveolar macrophages (AM) are antigen-presenting cells that have an important immune effector function in the lung. We have previously shown that AM produce a specific interleukin-1 (IL-1) inhibitor of 20 to 25 kD that blocks biologic activities of IL-1 alpha and IL-1 beta such as prostaglandin E2 production by fibroblasts. This inhibitor acts as a receptor antagonist (IL-1ra) by binding to the IL-1 receptor. We are now presenting evidence that the natural AM-derived IL-1ra is immunologically identical to IL-1ra cloned from human peripheral blood monocytes and shows a band at 20 kD compatible with the natural glycosylated IL-1ra. No constitutive expression of IL-1 mRNA was detected when analyzed by Northern blot immediately after bronchoalveolar lavage from six control patients. Comparison of in vitro kinetics of IL-1ra, IL-1 alpha, and IL-1 beta analyzed during culture in the presence or absence of phorbol myristate acetate revealed that their mRNA expression was asynchronous. IL-1 alpha and IL-1 beta mRNA were expressed after as little as 15 min, whereas IL-1ra mRNA was detectable only after 3 h in culture. The production of IL-1ra was measured by enzyme-linked immunosorbent assay and compared with that of IL-1 alpha and IL-1 beta. In freshly isolated AM (10(6)/ml), cell-associated IL-1ra was present in an average amount of 2.0 +/- 0.5 ng/ml, i.e., 25 and 100 times more than IL-1 alpha and IL-1 beta, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Inter&kin 1 (IL-l), present in high amounts in normal human skin without any sign of inflammation, suggests a complex mechanism by which its bioactivity is regulated. The specific receptor antagonist of IL-1 (IL-lra) was analyzed in human skin, sweat and cultured keratinocytes. Extracts of both skin and cultured keratinocytes blocked the binding of ['2sI]IL-1 to its receptor whereas sweat did not. The inhibitory activity was cell-associated, was not secrctcd by cultured keratinocytes, and IL-lra mRNA was identified in these cells. There was an inverse relationship between the level of IL-lra and that of IL-la andj3 since extracts of differentiating kerdtinocytes (DK) and higher IL-lra levels and expressed more mRNA for IL-lra than non-differentiated keratinocytcs (NDK), whereas NDK contained 4 times more IL-la and /? proteins than DK. This association of cell differentiation with a shift in agonist/antagonist ratio might be related to important autocrine or paracrine functions of IL-I in normal and inflamed human skin