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Secretory products of macrophages.

Interleukin-2 (IL-2), the first of a series of lymphocytotrophic hormones to be recognized and completely characterized, is pivotal for the generation and regulation of the immune response. A T lymphocyte product, IL-2 also stimulates T cells to undergo cell cycle progression via a finite number of interactions with its specific membrane receptors. Because T cell clonal proliferation after antigen challenge is obligatory for immune responsiveness and immune memory, the IL-2-T cell system has opened the way to a molecular understanding of phenomena that are fundamental to biology, immunology, and medicine.

https://science.sciencemag.org/content/sci/240/4856/1169.full.pdf

Interleukin-2: inception, impact, and implications.

Interleukin 1 (IL 1) is a polypeptide that is produced after infection, injury, or antigenic challenge. Although the macrophage is a primary source of IL 1, epidermal, epithelial, lymphoid, and vascular tissues synthesize IL 1. When IL 1 gains access to the circulation, it acts like a hormone and induces a broad spectrum of systemic changes in neurological, metabolic, hematologic, and endocrinologic systems. Some of the IL 1 that is synthesized remains associated with the plasma membrane and induces changes in local tissues without producing systemic responses. IL 1 affects mesenchymal tissue remodeling where it contributes to both destructive and repair processes. IL 1 activates lymphocytes and plays an important role in the initiation of the immune response. Receptors for IL 1 have been identified, but receptors are scarce and their affinities often do not match the potency of the biological response. The most consistent property of IL 1 is up-regulation of cellular metabolism and increased expression of several genes coding for biologically active molecules. IL 1 is a highly inflammatory molecule and stimulates the production of arachidonic acid metabolites. IL 1 also acts synergistically with other cytokines, particularly tumor necrosis factor. The multitude of biological responses to IL 1 is an example of the rapid adaptive changes that take place to increase the host's defensive mechanisms.

Biology of interleukin 1.

There is more than one interleukin 1.

Publisher Summary Interleukin-1 (IL-1) and tumor necrosis factor (TNF) participate in self-augmentation induction mechanisms. Recombinant human IL-1 and TNF are each capable of inducing the production of their respective molecules as well as each other. IL-1 and TNF both induce IL-6. The target cells include: monocytes, endothelial cells, smooth muscle cells, and B cells. The concentrations of IL-1 and TNF that stimulate their own production in this self amplification cycle are within the range (1-10 ng/ml) of what has been measured in the supernatant media of cultured cells stimulated with viruses, bacterial toxins, and active complement components, and of immune complex. The ability of interferon-y to suppress IL-l-induced IL-1 production takes place in the presence of cyclo-oxygenase inhibition. Similarly, the ability of corticosteroids to reduce the transcription of IL-1 messenger RNA (mRNA) also takes place in the presence of cyclooxygenase inhibition. IL-1 is the prototype of a group of biologically potent polypeptides with molecular weights between 10,000 and 30,000. Because these substances are produced by a variety of cells and act on many different cell types, there is a growing acceptance of the terminology “cytokines,” rather than “lymphokines” or “monokines.” Of the various “cytokines,” several share the ability to stimulate or augment cell proliferation, initiate the synthesis of new proteins in a variety of cells, and induce the production of inflammatory metabolites. IL-1 is biologically similar to tumor necrosis factor (TNF), lymphotoxin, IL-6, fibroblast growth factor (FGF), platelet derived growth factor (PDGF), and transforming growth factor- β (TGF-β)

Interleukin-1 and its biologically related cytokines.

Human and mouse lymphoid cells, stimulated by phytohemagglutinin (PHA) or lipopolysaccharide W (LPS), release supernatant factor(s) which are mitogenic for mouse thymocytes and which potentiate their responses to PHA or concanavalin A (Con A), The term LAF (lymphocyte-activating factor) is proposed for this activity. LAF not only enhances the mitotic responses of the less dense thymus subpopulations (A, B, and C) separable on discontinuous bovine serum albumin (BSA) gradients but also gives substantial responses in the otherwise inert cells of the denser fractions D and P. LAF does not exert a potentiating stimulatory effect on the responses of unfractionated mouse spleen cells, but does act synergistically with PHA on nonadherent spleen cells and on spleen cells of mice of several strains 5 days after irradiation and injection of thymocytes. Similarly LAF, which has no visible effect on unfractionated human peripheral blood cells, strongly potentiates the PHA response of column-purified lymphocytes, when these are cultured at low concentration. We conclude that LAF stimulates both central and peripheral T lymphocytes and enhances their responses to other stimulants.

/pdf/potentiation-of-the-t-lymphocyte-response-to-mitogens-i-the-3q5vm3i8dv.pdf

Potentiation of the t-lymphocyte response to mitogens : i. the responding cell

Effective supernatants (SUP), which potentiate mouse T-cell responses to phytohemagglutin (PHA), are obtained from cells of several species (human, rabbit, rat, mouse) and indeed from syngeneic spleen, thymus, or bone marrow cells. Unstimulated cells release some SUP activity but more is produced after stimulation. Lipopolysaccharide (LPS) produced very active SUP in all cultures tested. PHA was similarly active on human leukocytes only, whereas concanavalin A (Con A) gave highly efficient SUP only with mouse spleen cells. SUP production is not correlated with a mitotic response of the donor cells and is observed in cultures unable to respond mitotically to the stimulant. Adherent mouse spleen cell populations, consisting largely or entirely of macrophages, produce active SUP, while nonadherent cells do not. Similarly, purification of human peripheral leukocytes on nylon columns, with removal of macrophages and other adherent cells, destroys their ability to produce SUP. The importance of indirect effects in stimulating mitotic responses of T cells is emphasized by the fact that the mitotic response of mouse thymocytes to LPS and its ability to potentiate the response of these cells to PHA disappears with removal of adherent cells from the thymocyte population. Conversely the production of SUP from spleen cells stimulated by Con A requires the presence of T cells.

https://rupress.org/jem/article-pdf/136/1/143/1084773/143.pdf

Potentiation of the t-lymphocyte response to mitogens ii. the cellular source of potentiating mediator(s)

Potentiation of the T lymphocyte response to mitogens. III. Properties of the mediator(s) from adherent cells.

Rats subjected to high doses of whole-body irradiation, with simultaneous shielding of the thymus or spleen, recovered at 3 wk the ability to develop delayed sensitization and to form hemagglutinating and precipitating antibody following foot-pad injection of BγG in complete adjuvant. Injection of BγG into the shielded thymus immediately after irradiation, in amounts between 20 γg and 40 mg, inhibited these response to later challenge partially or completely. A comparable effect on immune responses to BγG was not seen after injection of heterologous antigen (Ea) intrathymically, BγG intraperitoneally, or BγG into the shielded spleen. However high doses (20 or 40 mg) of antigen given by the latter routes resulted in some diminution of later response. Arthus reactivity recovered partially in the spleen-shielded group and was readily suppressed by intrasplenic administration of antigen.

https://rupress.org/jem/article-pdf/124/2/127/1082471/127.pdf

Role of the thymus in tolerance iii. tolerance to bovine gamma globulin after direct injection of antigen into the shielded thymus of irradiated rats

BACILLUS Calmette-Guerin (BCG) is of considerable value as a non-specific adjuvant in the immunotherapy of neoplasia1–6. Although the striking preponderance of macrophages at the site of rejection elicited by intralesional BCG is support for their function as effector cells, we present evidence here for an additional role of the macrophage. Under the influence of systemically (intravenously) administered BCG, macrophages markedly stimulated thymus-derived (T) killer cells involved in lymphocyte-mediated cytotoxicity (cell-mediated immunity, CMI) in vitro.

Igal Gery

Papers

Potentiation of the t-lymphocyte response to mitogens : i. the responding cell

Potentiation of the t-lymphocyte response to mitogens ii. the cellular source of potentiating mediator(s)

Potentiation of the T lymphocyte response to mitogens. III. Properties of the mediator(s) from adherent cells.

Role of the thymus in tolerance iii. tolerance to bovine gamma globulin after direct injection of antigen into the shielded thymus of irradiated rats

On the mode of action of BCG.