The long-term objective of this research is to delineate the mechanisms hereby macrophage-secreted prostanoids (i.e. prostaglandins and thromboxanes) inhibit the activation of normal B cells and B lymphomas. First, selected prostanoids will be examined for their ability to promote B cell unresponsiveness, in conjunction with antigen-specific signals. This will be accomplished using an in vitro assay and purified hapten-specific B cells. Second, the role of B cell receptors for antigen and for the Fc portion of immunoglobulin in prostaglandin(PG)-enhanced negative signalling will be determined. This is important because in the presence of PG, cells may be negatively signalled or growth- inhibited via sIgM or Fc receptors. Third, since PGE2 inhibits macrophage activation, it may similarly block B cell activation. The effects of PGE2 on the activation of normal B cells and B lymphomas, stimulated by IL-4 or anti-IgM reagents, will be assessed. Activation will be monitored by increases in size, induction of membrane IL-I and class II expression. Inhibition of these events by PG may block proliferation, differentiation and ability to present antigen. Fourth, the presence of high or low affinity receptors for PGE2 will be examined using B lymphomas. Some lymphoma clones are growth-inhibited by PGE2, whereas others are resistant. The presence of PGE2 receptors on B lymphomas may confer susceptibility to this prostanoid. A binding assay will be used to detect this receptor and to determine whether its expression is altered by cell activation. Since relatively little is known about how arachidonic acid metabolites like PGE2 affect normal and neoplastic B cells, this research proposal would help fill that gap. Furthermore, understanding how prostanoids regulate B lymphomas may provide an avenue for new strategies to inhibit their growth in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA042739-05
Application #
3184286
Study Section
Immunobiology Study Section (IMB)
Project Start
1986-03-01
Project End
1994-03-31
Budget Start
1990-04-01
Budget End
1991-03-31
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Rochester
Department
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Brown, D M; Phipps, R P (1997) Prostaglandin E2 mediated apoptosis in subsets of malignant B lymphoma cells. Adv Exp Med Biol 400B:565-70
Borrello, M A; Phipps, R P (1996) Differential Thy-1 expression by splenic fibroblasts defines functionally distinct subsets. Cell Immunol 173:198-206
Borrello, M A; Phipps, R P (1996) The B/macrophage cell: an elusive link between CD5+ B lymphocytes and macrophages. Immunol Today 17:471-5
Gaspari, A A; Sempowski, G D; Chess, P et al. (1996) Human epidermal keratinocytes are induced to secrete interleukin-6 and co-stimulate T lymphocyte proliferation by a CD40-dependent mechanism. Eur J Immunol 26:1371-7
Silvera, M R; Phipps, R P (1995) Synthesis of interleukin-1 receptor antagonist by Thy-1+ and Thy-1- murine lung fibroblast subsets. J Interferon Cytokine Res 15:63-70
Brown, D M; Phipps, R P (1995) Characterization and regulation of prostaglandin E2 receptors on normal and malignant murine B lymphocytes. Cell Immunol 161:79-87
Fries, K M; Sempowski, G D; Gaspari, A A et al. (1995) CD40 expression by human fibroblasts. Clin Immunol Immunopathol 77:42-51
Roper, R L; Brown, D M; Phipps, R P (1995) Prostaglandin E2 promotes B lymphocyte Ig isotype switching to IgE. J Immunol 154:162-70
Borrello, M A; Phipps, R P (1995) Fibroblasts support outgrowth of splenocytes simultaneously expressing B lymphocyte and macrophage characteristics. J Immunol 155:4155-61
Sempowski, G D; Beckmann, M P; Derdak, S et al. (1994) Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol 152:3606-14

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