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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

A murine retroviral vector, LSNLsrc, has been constructed and examined for its ability to induce growth factor independence in cells normally dependent on interleukin 2 (IL-2) or interleukin 3 (IL-3) for growth. The LSNLsrc vector coexpressed the v-src gene of Rous sarcoma virus and the neo gene from transposon Tn5, allowing infected cells to be selected on the basis of G418 resistance. The murine cell lines CTLL-2 and FD.C/1, which are dependent for growth on IL-2 and IL-3, respectively, were both readily infected with the LSNLsrc virus. LSNLsrc-infected, G418-resistant cultures of FD.C/1 cells were able to give rise to IL-3-independent progeny, but all G418-resistant CTLL-2 cells retained normal IL-2 dependence. The induction of IL-3 independence by v-src was not a direct event, since limiting dilution analysis of the LSNLsrc-infected FD.C/1 cells showed that most of them were IL-3 dependent, despite expression of v-src mRNA and active pp60v-src kinase. However, clones selected from this population in the presence of IL-3 were able to undergo a subsequent progression event and generate IL-3-independent progeny. The generation of factor-independent variants in the clonal cultures was a rare event, as witnessed by the death of most of the cells in each clone when IL-3 was withdrawn. Together, these data indicate that a secondary event, in addition to v-src expression, was required to generate IL-3-independent growth. No evidence was found for an autocrine mechanism of transformation involving IL-2, IL-3, interleukin 4, or granulocyte-macrophage colony-stimulating factor.
Mol Cell Biol 1987 Oct
PMID:Nature and specificity of lymphokine independence induced by a selectable retroviral vector expressing v-src. 311 87

We have previously reported that BSF-1 and an alloantibody to the B-cell differentiation antigen Lyb2 induce class II gene expression in two Ia negative pre-B-cell lines. Two questions were asked in these studies. The first question is whether the different stimuli which we and others have shown to induce class II expression in B-cells act via the same signal transduction mechanisms. The second question is whether the traditionally accepted pathway of B-cell differentiation, as defined by immunoglobulin (Ig) gene rearrangement, is applicable to other events that occur during B-cell differentiation. In this report, we have therefore examined a large panel of pre-B-cell lines at different stages of Ig gene rearrangement in an attempt to 1) identify the stage in B-cell development where class II gene expression occurs and where it becomes inducible by BSF-1 or anti-Lyb2, and 2) compare the signal transduction mechanisms used by these ligands. The majority of pre-B-cell lines tested did not express BSF-1 receptors and were consequently noninducible for class II by BSF-1; such cell lines were, however, inducible for class II expression by anti-Lyb2 and, in addition, by antibodies to the B220 membrane glycoprotein. The induction of class II molecules by BSF-1 and by anti-Lyb2 and anti-B220 differed in several respects: 1) Induction by anti-Lyb2 and anti-B220 did not require the presence of BSF-1 receptors; 2) BSF-1 selectively induced class II antigen expression while anti-Lyb2 and anti-B220 induced the expression of other surface markers as well; and 3) PGE2 inhibited BSF-1 but not antibody-mediated class II induction. Finally, the presence of receptors for BSF-1 and the baseline expression of cell surface Ia was shown to be unlinked to Ig gene rearrangement and expression in this series of pre-B-cell lines. The independent regulation of Ia and Ig genes observed here may reflect a branching rather than a linear pathway for B-cell differentiation. The differentiation of pre-B-cells to mature Ig-secreting cells should probably not be defined solely by rearrangement of Ig genes, since this is likely to represent an oversimplified view of B-cell differentiation.
J Mol Cell Immunol 1988
PMID:Differential induction of class II gene expression in murine pre-B-cell lines by B-cell stimulatory factor-1 and by antibodies to B-cell surface antigens. 315 Oct 65

The synthetic immunomodulator muramyl dipeptide (MDP) has previously been shown to be able to synergize with lymphokines in enhancing the specific immune response of purified splenic B cells. Here, we have examined the effect of MDP in the process of B cell activation. We found that MDP alone was ineffective on the proliferation of either murine resting or in vivo activated B cells, whereas it enhanced the DNA synthesis of B cells once stimulated with anti-IgM antibodies. In agreement with these findings, cell cycle analysis by flow cytometry after acridine orange staining indicated that MDP by itself could not trigger the entry into the G1 phase of the cell cycle of nonactivated B lymphocytes. In contrast, in the presence of anti-IgM antibodies plus BSF-1, MDP promoted further cell cycle progression preferentially into the G1B compartment and also through the G2/M phase. A kinetic study showed that MDP was the most effective when added after the activation of B cells by anti-IgM antibodies plus BSF-1. Our present results suggest that functional receptors for MDP may be expressed on already cycling B cells.
Mol Immunol 1988 Apr
PMID:The synthetic immunomodulator muramyl dipeptide (MDP) can stimulate activated B cells. 326 Sep 89

In this work we have addressed two questions. Does switch recombination occur before membrane expression or only concomitantly with induction to high rate synthesis and secretion of IgG? Does interleukin-4 induce switch to IgG1 or maturation of already switched cells? To answer these questions we used the DNA synthesis inhibitor hydroxyurea (HU) to analyze the requirements for DNA replication in the induction of membrane expression or high rate secretion of all IgG subclasses by cultures of mouse spleen cells stimulated by lipopolysaccharide (LPS) and supplemented with IL-4, the absolute numbers of cells bearing membrane bound IgG was always decreased by HU, indicating that immunoglobulin class switching requires DNA replication. IL-4 did not augment the numbers of cells expressing any IgG isotype. In contrast, the number of high rate secretors of all IgG isotypes was not affected by HU, except in the case of IgG3 and IgG2b shortly after stimulation. Addition of IL-4 resulted in an increased number of secretory cells, and also this effect was resistant to HU. Thus, for any isotype, treatment with HU or IL-4 increased the frequency of secretory cells relative to the surface positive population. This data indicates that: 1) IL-4 is a broad range, non isotype-specific maturation factor for LPS-activated B cells; 2) induction to high rate secretion has a negative effect on proliferation; and 3) immunoglobulin class switch, but not induction to secretion of any immunoglobulin isotype, requires DNA replication, suggesting that switch recombination had to occur before expression of IgG in the membrane-bound form.
J Mol Cell Immunol 1988
PMID:Membrane expression of IgG but not maturation to secretion requires DNA replication. 326 37

A synthetic DNA construct has been developed as a standard molecule whereby murine cytokine mRNA molecules can be quantified by the reverse transcription-polymerase chain reaction (RT-PCR). The construct, designated Cytoquant 1, allows the quantification of murine IL-1 alpha, IL-2, IL-3, IL-4, IL-5, IL-6, IL-10, IFN-gamma, TNF-alpha, TGF-beta, GM-CSF, CD4, CD8, HPRT and beta-actin mRNA levels. This technique is based on the amplification of a transcribed RNA molecule from Cytoquant 1 as an internal standard control in both the RT and PCR reactions. The quantification data from these analyses are expressed in absolute values, i.e. molecules/cell, which allows the data derived from separate experiments to be compared. In this study, mRNAs encoding beta-actin, IL-10, IFN-gamma and GM-CSF have been quantitated in both Th1 and Th2 cell clones with, and without, stimulation. The quantitative analysis data are highly reproducible and cytokine mRNA concentrations are reflective of restricted cytokine secretion patterns. Furthermore, constitutive cytokine mRNA levels are detectable in resting cells, eliminating the need for exogenous stimulation. The high degree of sensitivity and accuracy make this methodology uniquely suited for the study of T-cell subset cytokine expression in both in vivo and in vitro biological models.
Mol Immunol 1995 Sep
PMID:A synthetic standard DNA construct for use in quantification of murine cytokine mRNA molecules. 747 5

Products of inducible nitric oxide synthase (iNOS) are known to be involved in lung injury following intrapulmonary deposition of immunoglobulin G immune complexes (IgG-ICx). In the current studies rat alveolar macrophages stimulated in vitro with murine interferon gamma (IFN-gamma), tumor necrosis factor alpha, interleukin 1 alpha, (IL-1 alpha), lipopolysaccharide (LPS), or IgG-ICx immunostained for iNOS and produced nitrite/nitrate- (NO2-/NO3-) in a dose- and time-dependent manner requiring availability of L-arginine. Under the same conditions, IL-4 and IL-10 reduced NO2-/NO3- generation. Type II alveolar epithelial cells, which were obtained from normal rat lungs and stimulated in vitro with IgG-ICx, LPS, or IFN-gamma, also immunostained for iNOS and generated NO2-/NO3-. Special techniques of bronchoalveolar lavage (BAL) were used to retrieve alveolar macrophages and type II alveolar epithelial cells. Under these conditions, intrapulmonary deposition of LPS yielded BAL fluids containing increased amounts of NO2-/NO3- and macrophages that spontaneously released NO2-/NO3- and stained for iNOS. After intrapulmonary deposition of IgG both macrophages as well as type II cells (retrieved by BAL) spontaneously produced NO2-/NO3- and both cell types immunostained for iNOS (approximately 20% of all type II cells and 35% of all alveolar macrophages). Using dual fluorescence staining for cell identification, frozen sections of lung tissue after IgG immune complex deposition revealed iNOS in both alveolar macrophages and type II cells. Finally, in the immune complex model of alveolitis, the appearance of iNOS in macrophages as well as macrophage production in vitro of NO2-/NO3- was dependent on the in vivo availability of tumor necrosis factor alpha, IL-1, and IFN-gamma. These studies suggest a dual cell source for nitric oxide in inflamed lungs and the requirements for iNOS of several cytokines.
Am J Respir Cell Mol Biol 1995 Jun
PMID:Lung sources and cytokine requirements for in vivo expression of inducible nitric oxide synthase. 753 74

Nitric oxide (NO) modulates the activity of a number of cell types, but little is known about its possible role in bone metabolism. In the present study we demonstrate that freshly isolated murine osteoblasts and an osteoblastic cell line express NO-synthase mRNA and release NO when stimulated with IL-1 or LPS, thus confirming the results of some recent reports using human and rat osteoblast-like cells. Synergistic effects were found between IL-1 and LPS or TNF. Enzyme induction was blocked by dexamethasone and IL-4. 1,25-dihydroxyvitamin D3 did not modify basal NO synthesis, but it markedly increased the cytokine-induced NO release. M-CSF, GM-CSF, IL-3, LIF, PTH, estradiol and calcitonin did not show significant effects on NO synthesis. NOS induction was blocked by various tyrosine-kinase inhibitors, geldanamycin and herbimycin A being the most potent. These results suggest that endogenous NO might participate in the regulation of bone remodeling at the local level, and may mediate some effects of vitamin D on bone. NO has recently been reported to inhibit osteoclastic bone resorption. The release of NO induced by bone-stimulating factors such as IL-1 may represent a protective mechanism helping to avoid excess resorption and preserve bone integrity in inflammatory conditions.
Mol Cell Endocrinol 1995 Jan
PMID:Mechanisms controlling nitric oxide synthesis in osteoblasts. 754 Sep 93

A murine pulmonary infection model utilizing intratracheal inoculation of Cryptococcus neoformans was used to analyze cytokines produced in response to opportunistic pathogens acquired via the respiratory tract. The specific question asked was whether early cytokine secretion in lung-associated lymph nodes (LALN) would predict whether this organism would be cleared from the lung. Lung colony-forming units (CFU) were analyzed in two strains of mice over 12 wk, and lung clearance was found to be strain dependent. C.B-17 mice reduced their lung CFU burden between day 7 and day 14 of infection, had significantly higher in lung CFU than C.B-17 mice. The capacity of cells from lungs and LALN to secrete cytokines was significantly different between the strains when assessed at day 7 and day 14 after inoculation. When compared with sensitive C57BL/6 mice 7 days after infection, resistant C.B-17 mice demonstrated (1) increased interferon-gamma secretion by LALN cells in vitro in response to media alone, heat-killed cryptococci, and the T cell mitogen concanavalin A and (2) increased interleukin (IL)-2 secretion by both LALN and lung cells in response to concanavalin A. IL-4 and IL-10 were comparable or undetectable in both mouse strains, whereas IL-5 was significantly higher in all lung cell cultures of C57BL/6 mice. Thus, an early regional Th1 immune response in C.B-17 mice correlated with resistance to the organism, whereas the absence of this response in C57BL/6 mice correlated with susceptibility.
Am J Respir Cell Mol Biol 1995 Oct
PMID:Early cytokine production in pulmonary Cryptococcus neoformans infections distinguishes susceptible and resistant mice. 754 79

In nasal biopsies from 17 adult patients with seasonal allergic rhinitis and from 10 healthy controls, cytokines were analyzed by reverse-transcriptase polymerase chain reaction (RT-PCR). The time-course study during winter included repeated local allergen provocation with subsequent nasal biopsies as well as biopsies taken during pollen season. The RT-PCR for CD44 yielded positive bands in 65 of 71 cases, in which cases mRNA for interleukins 2, 4, and 5 (IL-2, IL-4, and IL-5) were thus investigated by means of seminested PCR. IL-4 mRNA was found almost exclusively in the allergic patients. During provocation a significant increase in IL-4 was noticed compared with controls (p = 0.043). Equally, during the natural pollen season, IL-4 mRNA expression was significantly higher in patients not using nasal corticosteroids compared with those who did (p = 0.011). No differences in IL-2 or IL-5 were observed between the groups. These findings also indicate, together with earlier observations of T-cell activation, a phenotype switch toward T-helper 2 (Th2) cells, and the accumulation (homing) of these T cells in the nasal mucosa, that T cells constitute the main source for IL-4 in the nasal mucosa. Therefore, allergic patients have an increased synthesis of IL-4 when provoked with the allergen, and during natural pollen season this synthesis can be downregulated by corticosteroids. Furthermore, this study exemplifies the versatility of molecular biology in surgical pathology and that even low-copy-number cytokine mRNA can be examined in routinely snap-frozen surgical specimens.
Diagn Mol Pathol 1995 Jun
PMID:Nasal messenger RNA expression of interleukins 2, 4, and 5 in patients with allergic rhinitis. 755 Dec 98


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