Biological activity of interleukin-16.
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Animals↗
Biomedical subjects
H Kornfeld
Publications and source records attributed to H Kornfeld.
Chemotactic activity of mycobacterial lipoarabinomannans for human blood T lymphocytes in vitro.
A crucial early event in tuberculosis is the ingestion of Mycobacterium tuberculosis (Mtb) by alveolar macrophages. Chemotactic factors released by infected macrophages are likely to initiate a granulomatous response, a key feature of host resistance to tuberculosis. To date, the role of mycobacterial products in regulating the granulomatous response has not been clearly defined. Here we report that the mycobacterial cell wall glycophospholipid lipoarabinomannan (LAM) could specifically induce human peripheral blood T cell chemotaxis in vitro. Both terminally mannosylated LAM isolated from Mtb and LAM lacking the terminal mannosyl units isolated from an avirulent mycobacterium could induce T cell migration in the absence of serum. In contrast, terminally mannosylated LAM isolated from Mycobacterium bovis BCG failed to induce T cell chemotaxis. These observations represent the first report that LAM is capable of directly inducing biologic responses in human T cells. Flow cytometry analysis revealed that CD4+, CD8+, and CD45RO+ lymphocytes were present in the migrating cell populations at ratios similar to those found in nonmigrating cells. The chemotactic response was found to require new protein synthesis, and could be blocked by inhibitors of protein tyrosine kinases at concentrations that did not affect random migration. Acyl groups at the reducing terminus of LAM appear to be required for the chemotactic activity of this mycobacterial glycolipid. Lastly, culture supernatants from human alveolar macrophages infected in vitro with a virulent strain of Mtb could induce T cell migration. Much of the migratory activity present in these supernatants could be blocked using a mAb against LAM, suggesting that LAM is one of the chemotactic factors released by Mtb-infected alveolar macrophages.
Adult↗
Human eosinophils elaborate the lymphocyte chemoattractants. IL-16 (lymphocyte chemoattractant factor) and RANTES.
Eosinophils and CD4+ lymphocytes are preferentially recruited into sites of allergic inflammation. A role for eosinophils in the recruitment of CD4+ lymphocytes has not been defined. We studied the capacity of human eosinophils to release chemoattractants for T lymphocytes. Supernatants of cultured eosinophils contained chemoattractant activity for lymphocytes, which was predominantly due to IL-16 (lymphocyte chemoattractant factor) and RANTES. With neutralizing Abs, eosinophil-derived lymphocyte chemotactic activity was diminished by a mean (+/- SEM) of 60 +/- 3% with polygonal anti-IL-16 Ab, 69 +/- 4% with anti-IL-16 mAb, 48 +/- 3% with anti-CD4 F(ab) (IL-16 receptor blockade), 40 +/- 4% with anti-RANTES mAb, and 88 +/- 5% with a combination of anti-IL-16 and anti-RANTES mAbs. IL-16 and RANTES were detectable in eosinophil-derived supernatants by ELISA. Eosinophils constitutively expressed mRNA transcripts for both IL-16 and RANTES detectable by reverse transcription-PCR and contained preformed IL-16 and RANTES demonstrable by ELISA of cell lysates and by immunocytochemistry of freshly isolated eosinophils. Thus, eosinophils are a source of two cytokines, IL-16 and RANTES, that are chemoattractants for lymphocytes as well as eosinophils. These data indicate that eosinophils could contribute cytokines to enhance the recruitment of additional populations of CD4+ lymphocytes and eosinophils.
Antibodies, Monoclonal↗
Interleukin 16 and its function as a CD4 ligand.
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Animals↗
Phagocytosis and growth inhibition of Cryptococcus neoformans by human alveolar macrophages: effects of HIV-1 infection.
OBJECTIVE: The purpose of this study was to investigate the in vitro processing of Cryptococcus neoformans by human alveolar macrophages from HIV-seropositive individuals compared with HIV-seronegative individuals. DESIGN AND METHODS: Bronchalveolar lavage (BAL) was performed on smoking and nonsmoking HIV-seropositive and seronegative volunteers. Lavage cells from the four groups were challenged in vitro with C. neoformans and assessed for fungal binding, phagocytosis, and growth inhibition. RESULTS: The results indicated that BAL cells from the smoking HIV-infected group had increased fungistatic activity compared with HIV-seronegative smokers (mean percentage growth inhibition +/- SD, 77.5 +/- 14.2 versus 59.1 +/- 16.6%; P = 0.015). However, late-staged HIV-infected patients (Centers for Disease Control and Prevention class C3) were found to have decreased fungistasis compared with early stage A patients (63.8 +/- 11.1 versus 83.0 +/- 2.2%; P < 0.05). BAL cells recovered from HIV- seronegative smoking volunteers demonstrated reduced fungistatic activity when compared with BAL cells from HIV- seronegative nonsmokers (56.8 +/- 8.8 versus 83.0 +/- 2.2%; P < 0.001). Smoking also induced a decrease in internalization of C. neoformans by alveolar macrophages as assessed by confocal laser microscopy in both HIV-seronegative and HIV-infected groups. CONCLUSION: We conclude that BAL cells from early stage HIV-1-infected individuals do not have an intrinsic defect in fungistasis of C. neoformans. In fact, it appears that BAL cells from HIV-seropositive people are activated for fungistasis in early HIV infection, although fungistatic activity declines as the disease progresses. Incidentally noted was the finding that smoking decreases the internalization of C. neoformans in both HIV-infected and HIV-seronegative individuals, suggesting the possibility that smoking might enhance the susceptibility to cryptococcosis.
Cells, Cultured↗
Interferon-gamma reduces the capacity of human alveolar macrophages to inhibit growth of Cryptococcus neoformans in vitro.
Cytokine stimulation of mouse and rat macrophages has previously been shown to enhance their capacity to phagocytose and inhibit the growth of Cryptococcus neoformans. To extend these observations to primary human macrophages, we investigated the anticryptococcal activity of human alveolar macrophages stimulated with interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha), or macrophage-colony stimulating factor (M-CSF). Neither TNF-alpha nor M-CSF had any effect on fungal growth inhibition compared with unstimulated macrophages. Alveolar macrophages stimulated with IFN-gamma demonstrated reduced fungistasis for C. neoformans compared with controls (49% +/- 15% versus 75% +/- 12%; mean % growth inhibition +/- SD, P < 0.001). Confocal laser scanning microscopy was used to assess binding and phagocytosis of yeast. No difference was observed between unstimulated macrophages and macrophages stimulated with any of the cytokines tested. These data suggest that the cytokine regulation of anticryptococcal macrophage functions in humans differs from the rat and mouse. Conclusions drawn from these models may not necessarily be applicable to human cryptococcosis. In particular, the effects of IFN-gamma on the interaction of human alveolar macrophages with C. neoformans was not predicted based on the mouse and rat macrophage responses.
Animals↗
Role of the eosinophil in allergic reactions.
The eosinophil may have several functions in health and in the pathogenesis of allergic and other diseases. Some roles of the eosinophil are based on the acute, effector responses of this cell, its capacity to generate biologically active lipid mediators and release its granule contents, including its distinctive cationic proteins. Whilst the effector responses of eosinophils are important for their contribution to the acute pathogenesis of allergic diseases, a fuller understanding of the eosinophil requires evaluation of the role this cell may play at tissue sites, especially submucosal sites, where the cell is normally localized in the absence of disease. Moreover, for the long-lived, tissue-resident eosinophil, definition of the interactions that occur between the eosinophil and other immune cells is germane to understanding the functions of eosinophils both in acute and chronic diseases. Many allergic diseases are characterized by heightened accumulation of eosinophils and are chronic ongoing diseases.
Animals↗
Histamine-induced secretion of lymphocyte chemoattractant factor from CD8+ T cells is independent of transcription and translation. Evidence for constitutive protein synthesis and storage.
We have reported previously that histamine induces the release of the CD4+ cell-specific lymphocyte chemoattractant factor (LCF) into the culture supernatants of CD8+ cells between 1 and 4 h following stimulation. To determine the mechanism of histamine-induced secretion of LCF, we evaluated the effects of inhibitors of gene transcription and translation on LCF production, and determined the effects of histamine stimulation on LCF mRNA induction and stability. The histamine-induced secretion of LCF from CD8+ cells was not associated with de novo synthesis of protein, nor did histamine have an effect on the induction or stability of LCF mRNA. Biologically active LCF was found in cell lysates of unstimulated CD8+ but not CD4+ T cells; however, LCF mRNA was detected at similar levels in both cell types. The only detectable lymphocyte chemoattractant present in unstimulated cells was LCF, and histamine induced the secretion of LCF, but no other lymphocyte chemoattractant activities, within 4 h. These studies demonstrate that histamine can act as a secretagogue for the protein LCF, which is constitutively synthesized and present in a biologically active form in CD8+ T cells. The rapid appearance of LCF induced by histamine may represent a mechanism for recruitment and activation for CD4+ cells in diseases such as asthma.
CD4-Positive T-Lymphocytes↗
The CD4-associated tyrosine kinase p56lck is required for lymphocyte chemoattractant factor-induced T lymphocyte migration.
Lymphocyte chemoattractant factor (LCF) is a polypeptide cytokine which induces both cell motility and activation of T lymphocytes. These LCF-induced events demonstrate an absolute requirement for the cell surface expression of CD4. Because many CD4-mediated T lymphocyte activation events have been demonstrated to require the association of the src-related tyrosine kinase p56lck with the cytoplasmic domain of CD4, we examined the role of p56lck in LCF-induced lymphocyte migration in a murine T cell hybridoma line expressing transfected human CD4. LCF induces the catalytic activity of CD4 associated p56lck at chemoattractant concentrations of cytokine. Hybridoma cells that express CD4 with cytoplasmic point mutations which uncouple the CD4-lck association lack both lck enzymatic activity and chemotactic responses to LCF. The enzymatic activity of lck however does not appear to be required for CD4-mediated migratory signal. First, the protein tyrosine kinase inhibitor herbimycin A blocked LCF-induced p56lck activation but had no effect on the LCF-induced motile response. Second, T cell hybridomas expressing a chimeric receptor combining the extracellular domain of human CD4 and murine p56lck which lacked the kinase domain had a normal LCF-induced motile response. We conclude from these observations that CD4-lck coupling is essential for LCF-induced T lymphocyte migration but the motile response is independent of the enzymatic activity of CD4-associated p56lck.
Animals↗
Interactions between human bronchoalveolar macrophages and Blastomyces dermatitidis conidia: demonstration of fungicidal and fungistatic effects.
The effects of human bronchoalveolar macrophages (BAMs) on Blastomyces dermatitidis conidia were investigated. Macrophage monolayers were incubated for 5 days with or without interferon (IFN)-gamma or macrophage colony-stimulating factor (M-CSF) before challenge with conidia for 48 h at 37 degrees C. Hyphal growth (germination) was inhibited 12% by resident BAMs (P < .05). In contrast, resident BAMs blocked conidial phase transition by 88% (P < .05). Intermediate forms, aggregates of large cells in clums (not conidia or yeasts by morphologic criteria), appeared after incubation with BAMs and grew into typical yeasts once removed from the BAMs. IFN-gamma and M-CSF inhibited the ability of BAMs to block phase transition but not germination. Human BAMs demonstrated fungicidal and fungistatic activity against B. dermatitidis conidia independent of reactive oxygen intermediates and had greater effects on phase transition than on germination. The phase transition-associated fungicidal and fungistatic activities of BAMs were inhibited by IFN-gamma and M-CSF.
Blastomyces↗
The effect of infection with human immunodeficiency virus on the anticryptococcal activity of lymphocytes and monocytes.
The effect of infection with human immunodeficiency virus (HIV) on the capacity of human lymphocytes and monocytes to inhibit and kill Cryptococcus neoformans in an 18-h assay was examined. In vitro infection of the Jurkat human T cell line with each of 3 HIV strains caused significant loss of anticryptococcal activity, which peaked 3-4 weeks after HIV infection. Lymphocytes from HIV-seropositive and -seronegative persons had similar activity, even if highly enriched for CD4 cells. The activity of lymphocytes from both seropositive and seronegative donors was increased by culture with interleukin-2 and phytohemagglutinin, but only activated lymphocytes from seronegative donors caused a reduction in C. neoformans colony-forming units. Both peripheral blood mononuclear cells and monocytes from HIV-positive persons had significantly reduced antifungal activity compared with cells from seronegative donors. Thus, under defined conditions, infection with HIV can impair the anticryptococcal activity of both lymphocytes and monocytes. Such qualitative defects may contribute, together with CD4 lymphocytopenia, to the particular susceptibility of HIV patients to cryptococcosis.
CD4 Antigens↗
Amphetamine, not MDMA, is associated with intracranial hemorrhage.
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Amphetamine↗
Early identification of interleukin-16 (lymphocyte chemoattractant factor) and macrophage inflammatory protein 1 alpha (MIP1 alpha) in bronchoalveolar lavage fluid of antigen-challenged asthmatics.
Accumulation of CD4+ interleukin (IL)-2R+ lymphocytes in the airways of asthmatics is generally attributed to the presence of chemoattractant cytokines. The precise mechanism for the initiation of the earliest CD4+ lymphocyte infiltration and activation is unknown. In this study, we describe for the first time the presence of lymphocyte chemoattractant activity in the bronchoalveolar lavage (BAL) fluid obtained from asthmatics 6 h after antigen challenge. The majority of the chemoattractant activity at this early time point is represented by IL-16 (lymphocyte chemoattractant factor), a CD4+ cell-specific chemoattractant and growth factor. In addition to IL-16, macrophage inflammatory protein 1 alpha (MIP1 alpha) chemotactic bioactivity was detected in significant levels. While IL-16, MIP1 alpha, and IL-8 were all identified by enzyme-linked immunosorbent assay, the great majority of the lymphocyte chemoattractant activity in the BAL fluid after antigen challenge is attributable to IL-16 and MIP1 alpha. There were no detectable levels of IL-16 nor MIP1 alpha in BAL fluid of antigen-challenged normal subjects nor atopic nonasthmatics nor in saline-challenged lobes from the asthmatics. The identification of multiple lymphocyte chemoattractants early after antigen challenge suggests a complex cellular, as well as chemoattractant cytokine, profile in initiating the CD4+ T cell-mediated inflammatory process that is specific for the atopic asthmatic phenotype.
Adult↗
The lymphocyte chemoattractant factor.
The LCF is a unique interleukin without significant homology to other interleukins or chemokines. It is a chemoattractant factor for all CD4+ cells and either uses CD4 as its receptor or utilizes a cell surface complex of molecules for which there is an absolute requirement for the presence of CD4. In addition to its chemoattractant activity, it is a growth factor for CD4+ T cells, inducing resting cells to enter G1, as evidenced by the expression of MHC II molecules and IL-2R. Once induced by LCF to express IL-2R, CD4+ T cells become competent to respond to LCF and progress through the cell cycle to proliferation. LCF's activity on CD4 cells defines a role for CD4 on the eosinophil and monocyte and broadens the scope of functions of CD4 on the T cell. In this regard it may have importance in human disease states that are characterized by increased numbers of activated CD4+ cells, such as sarcoidosis, rheumatoid arthritis, or asthma. Likewise, it may play a key role in monocyte and eosinophil chemotaxis into tissues, being important in the latter in concert with hematopoietic factors that increase the available eosinophil pool.
CD4 Antigens↗
Regulation of endothelial cell glyceraldehyde-3-phosphate dehydrogenase expression by hypoxia.
Exposure of endothelial cells (EC) to hypoxia results in the increased expression of a distinct set of proteins with molecular masses of 56, 47, 39, 36, and 34 kDa. Their induction appears to be unique to EC and the stress of decreased oxygen tension. To understand the mechanism(s) and significance of the up-regulation of these proteins we have identified the 36-kDa protein by limited amino-terminal amino acid sequencing. The 21-amino acid sequence from the bovine protein exhibited 90.5% identity with the human sequence of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Northern blot analysis showed that the time course and extent of EC GAPDH mRNA up-regulation correlated with the increase in 36-kDa protein synthesis. Nuclear runoff analysis demonstrated that this increase in GAPDH expression is regulated, in part, at the transcriptional level; however, the increase in the rate of transcription did not account for the entire mRNA accumulation, suggesting that GAPDH, like other hypoxia-regulated proteins, is posttranscriptionally regulated. Subcellular fractionation of hypoxic EC showed up-regulation of the 36-kDa protein in the cytoplasmic fraction and, to a lesser extent, in the nuclear fraction. The up-regulation of GAPDH in EC may be related to their relative hypoxia tolerance. Alternatively, the up-regulation of GAPDH in EC during hypoxia may be related to the potential nonglycolytic functions of this enzyme.
Amino Acid Sequence↗
Molecular and functional analysis of a lymphocyte chemoattractant factor: association of biologic function with CD4 expression.
Lymphocyte chemoattractant factor (LCF) is a lymphocyte cell product that stimulates a migratory response in CD4+ lymphocytes, monocytes, and eosinophils. In concert with its chemoattractant activity, LCF induces human T-lymphocyte expression of interleukin 2 receptor. Here we describe the molecular cloning of cDNA encoding human LCF. It is a novel interleukin with no significant homology to any previously described cytokine families. There is an absolute requirement for both autoaggregation of LCF monomers and for membrane-expressed CD4 molecules for LCF-induced migration in lymphocytes.
Amino Acid Sequence↗
Production of tumor necrosis factor alpha in human leukocytes stimulated by Cryptococcus neoformans.
Tumor necrosis factor alpha (TNF-alpha) is a key mediator of inflammation and may promote human immunodeficiency virus replication in latently infected cells. Since cryptococcosis often is associated with aberrations in the host inflammatory response and occurs preferentially in persons with AIDS, we defined the conditions under which human leukocytes produce TNF-alpha when stimulated by Cryptococcus neoformans. Peripheral blood mononuclear cells (PBMC) produced comparable amounts of TNF-alpha following stimulation with C. neoformans and lipopolysaccharide. Detectable TNF-alpha release in response to C. neoformans occurred only when fungi with small-sized capsules were used and complement-sufficient serum was added. Fractionation of PBMC established that monocytes were the predominant source of TNF-alpha. TNF-alpha gene expression and release occurred significantly later in PBMC stimulated with C. neoformans than in PBMC stimulated with LPS. C. neoformans was also a potent inducer of TNF-alpha from freshly isolated bronchoalveolar macrophages (BAM). Upon in vitro culture, BAM and monocytes bound greater numbers of fungal cells, yet their capacity to produce TNF-alpha following cryptococcal stimulation declined by 74 to 100%. However, this decline was reversed if the BAM and monocytes were cultured with gamma interferon. These data establish that C. neoformans can potently stimulate TNF-alpha release from human leukocytes. However, several variables profoundly affected the amount of TNF-alpha released, including the type of leukocyte and its state of activation, the size of the cryptococcal capsule, and the availability of opsonins.
Cryptococcus neoformans↗
Cytokine binding to CD4+ inflammatory cells: implications for asthma.
While LCF is present in BAL early after antigen challenge, we know little about its other potential effects beyond CD4+ T cell, monocyte, and eosinophil chemotaxis and monocyte and CD4+ T cell activation. The work described here focuses on the hypothesis that the secreted protein products of T cells participate in the airway inflammatory process that underlies human asthma, and in particular that LCF could play an early role because of the unusual responsiveness of LCF-producing T to histamine. To date, most studies have addressed the measurement of cytokines derived from CD4+ T cells (e.g., IL-2, IL-3, IL-4, IL-5, and GM-CSF) in the airways of asthmatics, and attempted to correlate the presence of protein or mRNA with the complexion of the inflammatory infiltrate. These studies have been based upon the reports that there are increased numbers of CD4+ T cells in the airways of asthmatics, and that the presence of eosinophils might correlate with the secretion of TH2-type cytokines like IL-3, -4, and -5. Using this information as a background, our work has approached the problem in an entirely different way. We have focused our attention on the early events in antigen-induced asthma that are responsible for CD4+ cell accumulation in the lung, including CD4+ T cells, eosinophils, and monocytes. We have attempted to identify mechanisms by which mast cell mediators, in particular histamine, might play a role in the secretion of chemotactic lymphokines that are selective for CD4+ cells by using CD4 itself as a chemotactic factor receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗