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Eosinophil infiltration is the hallmark of allergic inflammatory events. However, the mechanisms governing the influx of eosinophils into the tissue at a site of an allergic reaction remains unclear. We have examined the interactions of eosinophils and neutrophils isolated from the same atopic donor with cultured human umbilical vein endothelial cell (EC) monolayers in the search for a mechanism for this selective eosinophil recruitment. First, the adherence of eosinophils and neutrophils to ECs stimulated with lipopolysaccharide, interleukin (IL)-1 alpha, and tumor necrosis factor-alpha were compared. Each mediator induced a similar dose-dependent enhancement of eosinophil adhesiveness for both eosinophils and neutrophils. Thus, although cytokine activation of ECs in the vasculature adjacent to an inflammatory site probably serves as an important focusing mechanism for the extravasation of inflammatory cells at this site, there does not appear to be any selective EC-dependent mechanism for eosinophil recruitment. Little or no effect on eosinophil and neutrophil adherence was observed with IL-3, IL-5, granulocyte/macrophage colony-stimulating factor, platelet-activating factor (PAF), leukotriene B4, or histamine. Second, the migration of eosinophils and neutrophils through an EC monolayer in response to chemoattractants was examined. PAF was found to selectively enhance eosinophil transendothelial migration at doses of 10(-7) to 10(-10) M, with optimal effect at 10(-8) M. This effect was gradient dependent and could be inhibited by WEB 2086, a specific PAF inhibitor. These results suggest that localized production of PAF may be a prime factor in the events leading to eosinophil accumulation at allergic inflammatory sites, and that selectivity for eosinophil recruitment occurs at the stage of transendothelial cell migration under the influence of cell-specific chemoattractants.
Am J Respir Cell Mol Biol 1992 May
PMID:Selective eosinophil leukocyte recruitment by transendothelial migration and not by leukocyte-endothelial cell adhesion. 131 35

Eosinophilia and eosinophil function are regulated by cytokines such as granulocyte/macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and interleukin-5 (IL-5). We have investigated the modulatory role of IL-5 on N-formyl-methionyl-leucyl-phenylalanine (FMLP), neutrophil-activating factor (NAF/IL-8), platelet factor 4 (PF4), and cytokine-induced chemotaxis of eosinophils from normal individuals. These eosinophils show a small chemotactic response toward PF4 but not to NAF/IL-8 and FMLP. Preincubation of eosinophils with low concentrations of IL-5 caused significantly increased responses toward PF4 and induced a significant chemotactic response toward FMLP and NAF/IL-8. In marked contrast, IL-5 (or IL-3) priming of eosinophils from normal donors resulted in a strong inhibition of GM-CSF-induced chemotaxis. A similar decrease in the chemotactic response toward GM-CSF was observed in eosinophils derived from allergic asthmatic individuals. This finding suggests that the latter eosinophils may have had a prior exposure to IL-5 (or IL-3). Washing of the cells after priming did not abrogate the inhibition of the GM-CSF response. Our data indicate that at low concentrations IL-5 is an important modulator of eosinophil chemotaxis, causing selective upregulation or downregulation of chemotactic responses toward different agents.
Am J Respir Cell Mol Biol 1992 Dec
PMID:Modulation of eosinophil chemotaxis by interleukin-5. 144 9

A number of investigators have demonstrated the association of CD5+ (Ly-1/Leu-1) B cells with autoimmunity, excessive B-cell proliferation, and transformation. Previous work from our laboratory, among others, suggests that the selective advantage of this frequently autoreactive B-cell subset is to provide activation signals to conventional antigen-specific B cells. If one current hypothesis is correct then the overrepresentation of CD5+ B cells in some diseases and their novel capacity to act as helper cells reflect the activities of a separate B-cell lineage. Because of these observations it is of particular interest to evaluate the factors which contribute to the maturation of the CD5+ B-cell subset. The possibility that CD5+ B cells produce a factor or factors capable of influencing their own development was the focus of the present investigation. Rather than attempt to obtain soluble factors from heterogeneous CD5+ B-cell populations which could be contaminated with cytokine secreting monocytes or which could require as yet undefined activation signals in order to secrete putative factors, we chose to evaluate the production of CD5+ B-cell inducing factor(s) by monoclonal CD5+ B-cell hybridomas. Added incentive to this approach was provided by the observation that these hybridomas elaborate a factor(s) which, together with (NPb) idiotype-specific antibody produced by the hybridoma, substitutes for CD5+ B-cell populations in activating antigen-specific (NPb idiotypic) B cells in vitro. Furthermore, because of the low percentage of CD5+ B cells in the spleen and their relatively low level of CD5 antigen expression, we employed a sensitive functional assay rather than surface antigen expression alone to detect small numbers of mature CD5+ B helper cells. With this previously described system it was possible to observe the induction of functional CD5+ B cells following a 40 h culture of apparently CD5- B-cell populations with a 19-22 kd factor or factors derived from a CD5+ B hybridoma. Data presented here and elsewhere suggest that this CD5+ B-cell inducing activity is not mediated by IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IFN-gamma, GM-CSF, or TNF. The role that such a B cell derived, B-cell directed factor may play in immunity and disease is discussed.
J Mol Cell Immunol 1990
PMID:A CD5+ B cell hybridoma derived factor(s), which induces maturation of CD5+, idiotype-specific B-cell populations. 169 80

Interleukin-5 contains only two cysteine residues both of which appear to be involved in the dimerisation of the molecule to form a disulphide-linked homodimer (Minamitake et al., J. Biochem. 107, 292-297, 1990). However, it remains unclear whether this linkage is necessary for the bioactivity of this cytokine. Site-directed mutagenesis was used to produce amino acid substitutions of either or both of the cysteines. The mutant proteins were all biologically inactive monomers, however when the two single mutant constructs were co-transfected, biologically active IL5 was produced. This is consistent with the dimer forming in a head-to-tail configuration.
Mol Immunol
PMID:Mutated interleukin-5 monomers are biologically inactive. 190 78

Although much has been learned about basal levels of immunoglobulin (Ig) transcription, the regulatory effects of cytokines and antigen (Ag) upon Ig expression in lymphocytes have not been fully characterized. We previously reported that Ag plus interleukin-5 (IL-5) caused increased steady-state Ig mRNA levels in Ag-specific cell lines. In this study, we have identified a region between -250 and -125 bp 5' of the Ig transcription start site that is necessary for the induction of increased mu mRNA levels by Ag plus IL-5. Mobility shift and UV cross-linking studies indicated that IL-5 plus Ag induced increased protein binding to this region. Furthermore, this sequence was found to be closely related to another A + T-rich sequence at -525 bp 5' of the transcription start site. Both sequences exhibited similar B-cell-specific and inducible protein binding. Our data suggest that treatment with IL-5 plus Ag induces several DNA-binding proteins, some of which may participate in increasing Ig transcription above basal levels by binding to sequences 5' of the octamer motif.
Mol Cell Biol 1991 Oct
PMID:Novel protein-DNA interactions associated with increased immunoglobulin transcription in response to antigen plus interleukin-5. 192 39

In the accompanying report (C. F. Webb, C. Das, S. Eaton, K. Calame, and P. Tucker, Mol. Cell. Biol. 11:5197-5205, 1991), we characterize B-cell-specific protein-DNA interactions at -500 and -200 bp upstream of the mu immunoglobulin heavy chain promoter whose abundances were increased by interleukin-5 plus antigen. Because of the high A + T/G + C ratio of these sequences and the consistent findings by others that enhancer- and promoterlike regions are often located near matrix-associated regions, we asked whether these sequences might also be involved in binding to the nuclear matrix. Indeed, DNA fragments containing the -500 binding site were bound by nuclear matrix proteins. Furthermore, UV cross-linking studies showed that the DNA binding site for interleukin-5-plus-antigen-inducible proteins could also bind to proteins solubilized from the nuclear matrix. Nuclear matrix-associated sequences have also been demonstrated on either side of the intronic immunoglobulin heavy chain enhancer. Our data suggest a topological model by which interactions among proteins bound to the promoter and distal enhancer sequences might occur.
Mol Cell Biol 1991 Oct
PMID:Identification of a matrix-associated region 5' of an immunoglobulin heavy chain variable region gene. 192 40

The region extending from -40 to -54 of the 5'-flanking region of the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) gene shows homology to sequences found in the 5'-flanking regions of other cytokine genes, those encoding interleukin-4 (IL-4), IL-5, and granulocyte colony-stimulating factor (G-CSF). This sequence element is referred to as conserved lymphokine element 0 (CLE0). Saturation mutagenesis of the CLE0 element indicates that in addition to the previously mapped region between -73 and -91 (CLE2+ GC box), the CLE0 element is necessary for induction of the mouse GM-CSF gene by phorbol myristate acetate/Ca ionophore (A23187) stimulation in T cells. The presence of the CLE0 element is necessary to observe stimulation of the transcription activity of the mouse GM-CSF promoter in vitro. Mobility shift assays revealed that this region forms an inducible DNA-protein complex, NF-CLE0, which consists of two complexes of similar mobility, NF-CLE0a and NF-CLE0b. NF-CLE0a and NF-CLE0b recognize the 3' half and 5' half of the CLE0 element, respectively, with an overlapping region recognized by both proteins. The recognition sequence of NF-CLE0a corresponds to the region required for induction by phorbol myristate acetate/A23187, while the recognition sequence of NF-CLE0b contains bases that have inhibitory activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Cell Biol 1991 Dec
PMID:Characterization of the mouse granulocyte-macrophage colony-stimulating factor (GM-CSF) gene promoter: nuclear factors that interact with an element shared by three lymphokine genes--those for GM-CSF, interleukin-4 (IL-4), and IL-5. 194 68

In recent years there has been considerable discussion of possible cross-regulatory mechanisms involving the immune system and the neuroendocrine system. Certainly, evidence of hormonal communication between these two systems would provide at least a partial explanation for the many anecdotal observations of physical and mental stress affecting disease course. In previous studies of a neoplastic lymphokine-responsive B cell clone, BCL1-3B3, we noted that these cells produced a lymphokine which could affect normal B cell growth and viability. Physical characterization of this lymphokine indicated that its molecular weight was identical to that of the neuroendocrine hormone adrenocorticotropin (ACTH). Since Blalock and colleagues had reported the production of ACTH by virally-infected B cells, we have investigated whether ACTH can functionally mimic the BCL1-3B3-derived lymphokine. The neuroendocrine hormone adrenocorticotropin (ACTH) can increase in vitro murine B lymphocyte proliferation when added at physiologically relevant concentrations between 10(-9) to 10(-11) M. ACTH does not mimic the action of any lymphokine known to be required for B cell proliferation such as IL-2, IL-4, or IL-5. ACTH requires the presence of one or more of these known B cell stimulatory factors for its action and the most marked increase in B cell proliferation were noted in assays for IL-5 activity where 10(-10) M ACTH increased thymidine incorporation up to five-fold. Using two-stage assays, we determined that ACTH acts during the latter stages of B cell activation (i.e., 3-4 days after initial stimulation with either the combination of IL-4, GAMIg-Sepharose, and IL-1 or the combination of DxS and IL-5). These data indicate a direct role for a stress-induced neuroendocrine hormone in modulating the course of a humoral immune response.
J Mol Cell Immunol 1990
PMID:Adrenocorticotropin (ACTH) functions as a late-acting B cell growth factor and synergizes with interleukin 5. 196 84

The peptide regulatory factors (PRFs), variously termed cytokines, lymphokines, interleukins, colony stimulating factors, interferons, etc., play a key role in the quantitative and qualitative regulation of protective responses--both in initiating immunological and inflammatory responses and in mediating and controlling the effector mechanisms that protect the body against micro-organisms. The process of immunization--involving antigen-presentation, lymphocyte-activation and clonal proliferation--depends on the action of a variety of PRFs. The function of accessory cells--the dendritic cells, macrophages, etc.--is stimulated by PRFs such as interferon-gamma, IL-1, TNF, GM-CSF and IL-4. The activation and expansion of T-lymphocytes requires IL-1, IL-2, IL-4, interferon-gamma, IL-6 and probably IL-7. Likewise, the activation and expansion of B-lymphocytes is regulated by PRFs such as IL-1, IL-2, IL-4, IL-5, IL-6, IL-7 and interferon-gamma. It is likely, although unproven, that PRFs also regulate the differentiation of B-cells to memory cells. Successful vaccination requires the immune system to be primed in such a way that natural challenge with a micro-organism or its products evokes an immune response that has the qualitative and the quantitative characteristics of both the humoral and cellular responses. Antibody class is critically influenced by particular PRFs, e.g. interferon-gamma regulates IgG2a; IL-4, IgE and IgG1; IL-5 and TGF-beta, IgA. PRFs are both produced by and regulate the T-lymphocytes which have key roles in protective responses--either directly, viz. the cytotoxic T-lymphocytes important in protection against certain viruses, or indirectly through the secretion of PRFs that regulate the speed, magnitude and quality of antibody cellular responses. The recruitment and enhanced production and function of granulocytic and phagocytic cells involves a number of T-lymphocyte PRFs including GM-CSF, IL-3, IL-5, IL-4, and IL-6. We do not have a good understanding of the fine-tuning of cellular responses nor of how infection with different pathogens results in different types of inflammatory responses; it is clear, however, that certain cellular responses are due to the action of specific PRFs, e.g. IL-3 induces a mastocytosis and IL-5 an eosinophilia. There is increasing evidence that the relative levels of different PRFs are important determinants of the effectiveness of responses.(ABSTRACT TRUNCATED AT 400 WORDS)
Mol Immunol 1991 Mar
PMID:Peptide regulatory factors and optimization of vaccines. 201 99

Human interleukin 4 (IL-4) upregulates Fc epsilon R2/CD23 expression on the surface of B lymphocytes. Here it is shown that IL-4 induces expression of CD23 mRNA in normal human B lymphocytes whereas recombinant IL-1, IL-2, IL-5, IFN gamma, IFN alpha 2b and semi-purified low molecular weight B cell growth factor were unable to do so. CD23 mRNA expression could be observed in B cells after 6 hr incubation with IL-4 and was maximal for 24-72 hr. Costimulation of the B cells with anti-IgM antibody enhanced the IL-4 induced CD23 mRNA expression. In contrast, IFN gamma and IFN alpha 2b inhibited IL-4 induced CD23 mRNA expression in normal B lymphocytes. Thus the regulatory effects of IL-4 and interferons on the CD23 membrane expression are linked to an increase and a decrease of CD23 transcripts respectively.
Mol Immunol 1990 Feb
PMID:Interleukin 4 and interferons alpha and gamma regulate Fc epsilon R2/CD23 mRNA expression on normal human B cells. 213 8


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