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Query: UNIPROT:P06889 (Mol)
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Recent advances in cellular and molecular biology have provided important new avenues to assess mechanisms of granuloma formation/regulation. For example, current studies have identified various cytokines that can exert a powerful influence on both immune and non-immune cells and dictate inflammatory processes. Some of these cytokines are potentially active during the initiation and maintenance of chronic inflammation, including tumor necrosis factor, interleukin 1, and a novel class of chemotactic cytokines. This latter group of mediators belongs to a super-gene family of immune signals that play a key role in the selective recruitment of inflammatory cells to an area of inflammation. The coordinated synthesis of these cytokines is likely important to the development of the granulomatous response. The participation of molecular signals produced by non-inflammatory cells, fibroblasts, and epithelial cells, also warrants special consideration. These "bystander" cells appear to possess effector cell functions and likely serve an important role in inducing pulmonary granulomatous inflammation. Thus, a clear understanding of the cells and molecular signals involved in the initiation and maintenance of chronic pulmonary inflammation will be necessary to assess lesion development and design more selective/effective therapies.
Am J Respir Cell Mol Biol 1989 Dec
PMID:Cellular and molecular aspects of granulomatous inflammation. 270 Mar 6

B cells can be activated by T-independent antigens or mitogens such as lipopolysaccharide (LPS) which will induce proliferation and differentiation of the B cells into Ig-secreting cells, without the intervention of T cells. The precise mechanism of T-independent proliferation and differentiation of B cells is still unclear. It is possible however that antigen-stimulated B cells may produce some factors which play a role in T-independent B-cell responses. In addition, since it has now been established that B cells can function as antigen-presenting cells, it is possible that they too secrete a molecule which is involved in the activation of T cells, analogous to IL-1 production by antigen-presenting macrophages. A number of human B-cell lines, as well as human normal B cells activated appropriately, have been shown to produce various cytokines, and similar studies are now being undertaken in the mouse. In the present study, six cloned murine B-cell lymphomas of different origin were analyzed for the presence of mRNA encoding a number of lymphokines by hybridization of specific cDNA probes to poly-A RNA, followed by the sensitive S1 nuclease digestion technique. The lymphokines included (IL-) 1, 2, 3, 4, 5, and neuroleukin. Whereas none of the lines expressed detectable levels of IL-2, IL-3, or IL-5 mRNA, all the lines expressed high levels of neuroleukin mRNA. Three of the lymphomas (CH12, CH31, and NBL) expressed low levels of IL-1 mRNA. The most striking finding was that one lymphoma, CH12, constitutively expressed IL-4 mRNA. This mRNA appeared to be functional, as IL-4 activity measured by the HT-2 T cell proliferation assay could be detected in supernatants collected from CH12 cells. The growth-inducing activity of CH12 supernatant on HT-2 cells could be completely blocked by an anti-IL-4 monoclonal (11B11), but not by an anti-IL-2 antibody (S4B6), consistent with our observations that CH12 cells produce IL-4 but not IL-2. CH12 cells were also found to express high affinity receptors for IL-4. Proliferation of CH12 cells was not affected by the addition of exogenous IL-4. Addition of anti-IL-4 antibodies to CH12 cells in culture caused a slight but reproducible increase in their proliferation at low cell numbers, which is probably not highly significant. These findings open the possibilities that murine B lymphocytes are capable of lymphokine production or alternatively that aberrant lymphokine production underlies B-lymphocyte transformation.
J Mol Cell Immunol 1989
PMID:Constitutive production of lymphokines by cloned murine B-cell lymphomas--CH12 B lymphoma produces interleukin-4. 278 29

An EBV transformed B-cell line was derived from peripheral blood cells from a single donor. B-cell clones were isolated from that line and analyzed for transcription of IL-1 genes, production of biologically detectable IL-1 and antigen presenting capabilities. One clone was found to secrete IL-1 activity into tissue culture medium, and to express the gene for IL-1 alpha. Three other clones were positive for cell surface IL-1 activity but no activity could be detected in culture supernatants. Those clones express the gene for IL-1 beta but not IL-1 alpha. All clones were approximately equal in their ability to present antigen to resting and primed T cells.
Mol Immunol 1987 May
PMID:Production of IL-1 alpha and IL-1 beta by clones of EBV transformed, human B cells. 282 86

Long-term synovial fibroblast cultures were exposed to interleukin 1 (IL-1) or prostaglandin E2 (PGE2). The normally spindle-shaped fibroblasts changed to stellate-shaped cells, resembling the HLA-DR-positive, collagenase-producing cells which are normally seen only in primary cultures from enzyme-digested rheumatoid synovial tissue. However, the IL-1- or PGE2-induced fibroblasts were not HLA-DR-positive. This suggests that these cell populations represent originally different cell lines or that the expression of HLA-DR antigens is not induced by the agents used. For further characterization of these stellate cells, the location of fibronectin and type I collagen was studied by specific antibodies and the pericellular coat around fibroblasts was visualized by the erythrocyte exclusion method. Both IL-1 and PGE2 treatments destroyed the intercellular fibronectin network. Type I collagen was detected as intracellular granules. The stellate fibroblasts were usually full of these granules in contrast to intact fibroblasts in which the number of collagen fluorescence granules varied greatly. The pericellular coat known to be formed mainly by hyaluronic acid was similar around spindle and stellate-shaped fibroblasts. Rheumatoid arthritis-derived fibroblasts did not differ from their non-rheumatoid counterparts in any of the experiments. The effect of IL-1 and PGE2 on fibroblasts simulates the interaction between mononuclear cells and fibroblasts in synovial stroma and also potentially the interactions between different cell types in synovial lining.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Connective tissue components in synovial fibroblast cultures exposed to interleukin 1 and prostaglandin E2. 287 May 82

Direct in vitro effects of IL-1 on hormone-dependent (MCF-7 and ZR-75-B) and independent (HS-578-T and MDA-231) human breast cancer cell proliferation were investigated in short-term and long-term cell cultures. For short-term (48 h) studies [3H]thymidine uptake was used as an index of proliferation, while for long-term (12 day) cultures actual cell numbers were determined. Initial studies, conducted with MCF-7 cells, demonstrated that both forms of recombinant human IL-1 (alpha and beta) at 10(-11) M inhibited [3H]thymidine uptake by MCF-7 by 70%, and by day 7 of the long-term study alpha and beta IL-1 at 10(-11) M inhibited MCF-7 cell growth by 80%. IL-1, while inhibiting the growth of another hormone-dependent breast cancer cell line; ZR-75-B, had no effect on the hormone-independent cell lines MDA-231 and HS-578-T. The differing proliferative responses of the hormone-dependent and independent cells to IL-1 may, in part, be due to the expression of IL-1 receptors on these cells, in that MCF-7 cells express IL-1 receptors [dissociation constant (Kd) = 2.0 x 10(-10) M; receptor density = 2,500 sites per cell and mol wt = 80,000] while the hormone-independent MDA-231 cells do not.
Mol Endocrinol 1988 May
PMID:Interleukin-1 directly regulates hormone-dependent human breast cancer cell proliferation in vitro. 297 Nov 35

The murine T-lymphoma cell line LBRM-33 is known to require synergistic signals delivered through the antigen receptor (Ti-CD3) complex, together with interleukin 1 (IL-1), for activation of IL-2 gene expression and IL-2 production. Although 12-O-tetradecanoylphorbol-13-acetate (TPA) was capable of replacing IL-1 as an activating stimulus under certain conditions, biologic studies indicated that TPA failed to synergize with Ti-CD3-dependent stimuli under conditions in which IL-1 was clearly active. Acute exposure to TPA and other active phorbol esters resulted in a concentration-dependent inhibition of the increases in phosphoinositide hydrolysis and intracellular free Ca2+ concentration stimulated by phytohemagglutinin or anti-Ti antibodies. TPA treatment induced no direct alteration of phospholipase C enzymatic activities in LBRM-33 cells. In contrast, both Ti-CD3 cross-linkage and TPA rapidly stimulated the phosphorylation of identical CD3 complex polypeptides, presumably via activation of protein kinase C. Exposure of LBRM-33 cells to TPA resulted in a time-dependent, partial down-regulation of surface Ti-CD3 expression. Thus, TPA treatment inhibited the responsiveness of LBRM-33 cells to Ti-CD3-dependent stimuli by inducing an early desensitization of Ti-CD3 receptors, followed by a decrease in membrane receptor expression. These studies indicate that phorbol esters deliver bidirectional signals that both inhibit Ti-CD3-dependent phosphoinositide hydrolysis and augment IL-2 production in LBRM-33 cells.
Mol Cell Biol 1988 Dec
PMID:Inhibition of T-cell antigen receptor-mediated transmembrane signaling by protein kinase C activation. 297 23

When 5-fluorouracil (5-FU) resistant bone marrow (BM) cells are depleted of B-cells and then cultured in insert chambers [separated from a layer of adherent BM (aBM) cells by a nucleopore membrane], no mature, lipopolysaccharide (LPS) reactive B-cells are formed. Factors acting on B-cell precursors are not produced unless nonadherent accessory cells have been cultured with aBM cells in the surrounding well. Moreover, soluble products are insufficient to induce differentiation of B-cell precursors unless the cells have been conditioned by direct contact with aBM cells. Such preconditioned precursors complete differentiation when cultured with IL-3 plus IL-1 in dishes coated with fibronectin. In cultures supplemented with IL-3, IL-1 and fibronectin, a pleomorphic layer of aBM cells is generated after a few days. This is not the case in cultures lacking IL-3. Therefore, an important function of IL-3 may be to recruit an adherent accessory cell type from the pool containing precursors of the B-cell as well as myeloid lineages. This view is further supported by experiments on the generation of colonies containing antibody secreting B-cells from day 15 fetal liver precursors which depends on soluble products secreted by aBM cells. When aBM cells established in the absence of IL-3 are present, more than one cell type (or cell product) is limiting. However, if aBM cell layers are generated in the presence of IL-3, only B-cell precursors seem to be limiting. Since macrophages play an important role in the aBM population, the effect of CSF-1 was investigated. Even though CSF-1 potentiates the effect of IL-3 and IL-1, it cannot replace these interleukins. Like IL-3, it may influence B-cell differentiation in an indirect manner by modifying the microenvironment. Another important function of macrophages seems to be related to the production of C3, which binds to CR2 after degradation. P14, a peptide of the CR2 binding C3d fragment, strongly inhibits maturation of B-cell progenitors. A larger CR2 binding peptide, P28, is inhibitory at low concn but stimulatory at higher concn. It is assumed that aggregated P28 may cross-link with CR2 and thereby transfer a differentiation signal to the cell.
Mol Immunol 1988 Nov
PMID:Functional maturation of murine B lymphocyte precursors--III. Soluble factors involved in the regulation of growth and differentiation. 306 30

The purpose of the study was to determine the temporal relationship between lymphocyte activating factor (LAF) activity and the acute-phase response, as measured by plasma fibronectin (Fn), C-reactive protein (CRP), and albumin levels in adjuvant arthritic rats. LAF activity as measured in the thymocyte costimulator assay, and plasma Fn, CRP, and albumin levels were measured during the acute (Day 3), intermediate (Day 10), and systemic (Day 17) phases of arthritic disease. On Day 3, supernatants from whole spleen cells of adjuvant-injected rats did not exhibit abnormal LAF activity. By Day 10, LAF activity in splenic supernatants from arthritics was significantly (P less than or equal to 0.05) higher than normal, although the increase was no greater than 60%. On Day 17 the LAF activity from arthritic rats had increased an average 300% compared to normals. In contrast to the time course of IL-1 activity, Fn and CRP levels in the arthritic rat were significantly higher than normal at all three time points, although there was a transient fall in Fn and CRP concentrations on Day 10. Plasma albumin levels in arthritic rats were subnormal (P less than or equal to 0.01) on Days 3, 10, and 17, although the concentration of plasma albumin on Day 10 was significantly higher than that measured on Day 3. The acute, intermediate, and systemic phases of adjuvant arthritic paw inflammation paralleled the abnormal profile of Fn, CRP, and albumin concentrations over time. However, LAF activity from arthritic rat spleen cells increased gradually and more closely coincided with the systemic appearance of the disease. Since the appearance of abnormal plasma protein levels in arthritic rats preceded the appearance of increased splenic LAF activity, it appears that there is no causal relationship between enhanced splenic LAF activity and early alteration of plasma Fn, CRP, and albumin levels.
Exp Mol Pathol 1988 Dec
PMID:Lymphocyte activating factor (LAF) and the acute-phase response in adjuvant arthritic rats. 314

The Fc region of IgG is known to be the source of small peptides possessing immunomodulatory function. Results are summarized showing the effect of synthetic peptides composed of surface exposed residues of C gamma 2 or C gamma 3 domains on different steps of human B lymphocyte activation cycle. Both the CH2 (289Thr-301Arg) and CH3 (407Tyr-416Arg) peptides as well as the whole Fc fragment enhanced the IgM synthesis of PWM or PMA + CaI activated lymphocytes. This effect was exerted at the early phase of B cell activation. The incubation of separated resting B cells with Fc fragments or CH2 peptides resulted in increase of cell volume and in expression of HLA-DR antigen. On the other hand, LIF production was induced both by CH2 and CH3 peptides. It was also shown that Fc peptides induce IL-1 release from monocytes. The results suggest that the CH2 and CH3 domain peptides exert their effect partly directly, by activating resting B cells, rendering the cells more susceptible to other stimuli; and moreover, by enhancing the humoral response by triggering the release of IL-1.
Mol Immunol 1988 Nov
PMID:Immunomodulatory effect of synthetic peptides corresponding to sequences within the CH2 and CH3 domain of human IgG1. 314 95

Both interleukin-1 alpha (IL-1 alpha) and IL-1 beta are initially translated as approximately Mr 30,000 polypeptides, lacking hydrophobic or signal sequence that could facilitate transmembrane translocation and release of mature IL-1 (Mr 17,500). The current study utilizes an antiserum specific for murine IL-1 alpha in order to investigate membrane associated IL-1 alpha polypeptides and possible postsynthetic modifications of the IL-1 alpha precursor, that might account for its intracellular transport. Cell surface iodination of endotoxin stimulated murine macrophages allowed the detection of IL-1 molecules in size similar to the IL-1 alpha precursor (Mr 33,000). Membrane bound IL-1 alpha was sensitive to degradation by serine esterase activity to yield IL-1 peptides of Mr 16,000 to 18,000. Endotoxin stimulated macrophages, but not unstimulated cells, incorporated 32PO4 into the IL-1 alpha precursor. The phosphate label of the IL-1 alpha precursor is resistant to hydroxylamine and alkaline phosphatase treatment. Released IL-1 is not phosphorylated. Approximately 10% of the phosphorylated IL-1 alpha precursor is membrane bound and associated with fractions enriched in lysosomal vesicles. These data are consistent with a model for mIL-1 expression, in which pro IL-1 alpha is post-synthetically modified to achieve intracellular transport and further suggest that mIL-1 may be a prerequisite for the release of IL-1.
Mol Immunol 1988 Nov
PMID:Structure and function of membrane IL-1. 326 77


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