Thymosin increases production of T-cell growth factor by normal human peripheral blood lymphocytes.

Abstract

The in vitro incubation of phytohemagglutinin-stimulated peripheral blood lymphocytes with thymosin results in a marked and reproducible increase in production of T-cell growth factor, which is dose dependent and most pronounced in the first 24 hr of culture. Incubation of lymphocytes with thymosin alone failed to induce any production of Tcell growth factor. The biological activity of thymosin fraction 5 cannot be attributed to the activity of thymosin a,, one of the well-characterized peptide components of fraction 5. These data provide the basis for (i) a potential mechanism for the in vivo immunorestorative effects of thymosin in primary and secondary immunodeficiencies and (ii) identification of an additional, but as yet undefined, immunoregulatory component of thymosin fraction 5.The lymphokines are a group of mediators elaborated by activated lymphocytes that have important effects in the cascade of events following lymphocyte stimulation. T-cell growth factor (TCGF), also referred to as interleukin 2 (IL-2), has been widely studied (1) and is known to influence Tcell maturation, production of other lymphokines such as yinterferon (y-IFN) (2), and induction of natural killer and Tcell cytolytic activity (3,4). Recent attention has been focused both on the lack of TCGF production in certain immunodeficiency states and on the immunoregulatory potential of TCGF in enhancing depressed natural killer and virus specific cytotoxicity (5).The thymosins are a family of thymic humoral factors that have been proposed as hormonal agents with important immunoregulatory effects (6). Thymosins, as well as other thymic preparations, are being tested extensively in vivo, as biological response modifiers in clinical trials and experimental models of primary and secondary immunodeficiencies, including acquired immunodeficiency syndrome (AIDS), autoimmune disease, neoplasia, and aging (7-11). The (12)(13)(14). The biological properties of two of these peptides, thymosins a1 and f34, have been studied extensively (12, 13). It has been suggested from earlier studies that these two peptides do not account for all the biological activity of the parent compound (15-17).Since F5 increases immune responsiveness in children with primary immunodeficiencies (7) and in cancer patients (10), and is being tested in clinical trials of autoimmune disease (9) and the pre-AIDS complex (8), we asked whether F5 functions, at least in part, by modulating TCGF production. It has been reported that F5 and thymosin a1 increase production of migration inhibition factor (MIF) in the mouse and guinea pig (18, 19) and production of a-and y-IFN in mice (20) and humans (21). Thymulin (FTS, facteur thymique serique), another thymic factor, has been shown to increase TCGF production by cells of nude mice (22). Grinblat et al. have reported increased TCGF production by thymic humoral factor (THF) in aged animals (23).In this paper, we report that F5 substantially and consistently augments production of TCGF by peripheral blood lymphocytes (PBL) ...

Thymosins, Lymphokines, and the Immunology of Aging

“…A comparison of PNA~ cells to peripheral lymph node cells shows similar effects, strongly suggesting that TF-5 is in fact acting upon a relatively mature pop ulation. These findings are consistent with our experiments with human PBL, which also show a marked enhancement of IL-2 production by TF-5 [67],…”

“…45] and THF [61] enhance 1L-2 production in nude and adult thymeclomized mice, respectively. Most re cently we have reported that TF-5 markedly enhances IL-2 production by human periph eral blood lymphocytes [67], TF-5 and TFX have been reported to play a role in regulation of hemopoiesis via T cell products and colony-stimulating factor (CSF) [1,52], This is a particularly intriguing obser vation since it is suspected that T cell progen itors decline in bone marrow of aged animals [59,60], but that proliferative potential of bone marrow stem cells is intact [25]. It has been proposed that there is not a decline in stem cell potential in aging, but rather a defect in regulation of stem cell proliferation [60].…”

Modulation of interleukin 2 receptor expression on normal human lymphocytes by thymic hormones.

“…Purified IL-2 can directly up-regulate synthesis and expression of its own receptors on PHAactivated T cells during the early phase of mitogen-induced IL-2R expression (10) and on cells whose IL-2R expression had declined (4). Since TF5 augments IL-2 production in response to PHA (18), it was possible that the increases in IL-2R expression observed in the presence of TF5 were due to IL-2-mediated up-regulation of IL-2R. To investigate this possibility, we incubated PBLs with PHA or OKT3 and TF5 in the presence of CsA.…”

“…In vivo, injection of thymosin a1, a synthetic peptide originally isolated in its native form from thymosin fraction 5 (TF5), a partially purified calf thymus preparation (12)(13)(14)(15)(16), increases IL-2 production in vitro and the response to IL-2 of spleen cells from old mice in response to mitogens (17). Further, TF5 increases in vitro IL-2 production by human lymphocytes in response to phytohemagglutinin (PHA) (18,19). Although the increased IL-2 production could account for some of the enhancement of the lymphocyte proliferation induced by thymic hormones, the critical role of the expression of IL-2R in proliferative responses prompted us to examine the modulation of IL-2R expression by TF5 in mitogen-stimulated lymphoid cells.…”

Synergism Between Thymosin Alpha One and Epidermal Growth Factor in the Stimulation of Rat Fibroblast Cell Proliferation: Cellular and Molecular Aspects

“…12,600 and 3.108, respectively) originally isolated from the thymus or its extracts [2], Tal is thought to be derived from ProTa, since its 28-aminoacid sequence is identical to that of the latter's N terminus [2,3], Thymic hormones regulate several T-cell responses [see review in ref. 4,5] and increase cellular-mediated immunity in immunosuppression models [6. 7], The participation of ProTa and Tal in nonlym phoid intracellular events was suggested by Eschenfeldt and Berger [8], who observed a significant increase in ProTa mRNA in fibro blast NIH 3T3 cells within the first 12 h after initiation of proliferation by serum refeeding, and a decrease in ProTa mRNA levels when proliferative quiescence was induced by se rum starvation.…”