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LTD4 induces no such suppressor cell activity. The magnitude of the suppressor cell activity generated by LTB4 is comparable to that seen with histamine, but the concentrations at which it occurs are orders of magnitude lower than those needed with the latter. LTB4-induced suppressor T cells can also inhibit immunoglobulin production by B cells and leukocyte migration inhibitory factor production by T cells.

When LTB4 induces the appearance of suppressor cells, the effective suppressor cells bear finally the CD8+ phenotype. Proliferation of CD4+ cells is inhibited by LTB4, whereas the proliferation of CD8* cells is enhanced. Further analysis of the cellular requirements for LTB4-induced suppressor cell activity reveals that, whereas only T cells need to interact with LTB4, the expression of their suppressor activity requires the presence of monocytes in the responding cell population. Only purified CD8+ T cells can bypass this requirement. For prein-cubated CD4+ T cells or unfractionated T cells, little suppression is seen in the absence of monocytes, whereas a helper effect is evident in the presence of monocytes plus the cyclo-oxygenase inhibitor indo-methacin. This phenomenon could be explained by a dual stimulation of monocytes to produce both PGs and interleukin-1 (IL-1) by LTB4-preincubated T cells. Indeed, LTB4-pulsed T cells release a soluble factor which stimulates monocytes to produce PGE2 and/or IL-1, and most of the activity of such T cell supernatants is attributable to interferon y (IFNy). LTB4 can indeed enhance, at nanomolar concentrations, IFNy production by CD41 T cells and inhibit IFNy production by CD8+ T cells. In the mouse, LTB4 (as well as other leukotrienes and AA itself) can replace a requirement for helper cells or IL-2 in IFNy production. LTB4 can also induce proliferation of IL-2-dependent T cells in the presence of suboptimal IL-2 and restore such proliferation after inhibition with lipoxygenase inhibitors or hydrocortisone. LTB4 can also induce T cells to produce IL-2 and IL-5 (Figure 1).

B lymphocytes

Purified human B cells show amplified proliferative responses to IL-2, IL-4 and B cell stimulatory factor, when exposed to picomolar concentrations of I.TB4. Immunoglobulin G (IgG) production is also enhanced by LTB4, but not by LTC4. Moreover, in the presence of IL-4, LTB4 stimulates IgE production, suggesting a central role for this mediator in allergy. In contrast, LTC4 can affect B cells directly and suppress Ig production. LTB4 also induces enhanced CD23 and major histocompatibility complex (MHC) class II antigen expression on B cells (Figure 1).

Suppressor cell Activity

IL-2 production IL-5 prodtdion IFNy pfottielion CDS' tylosis activity

T cell

6 cell

6 cell

T cell

LTB,

Pro He ration IgG producljon

IL-4-dependent IgE production CD?3 expression MHC II expression

NK eel

Cytotoxicity IL-2fl|l expiation

NK eel

Macrophage lL-6 production TNF« production Cytoto*K(y 07 production PGE.n pfüducllan

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