Tuftsin (an Ig-associated tetrapeptide) triggers the immunogenic function of macrophages: implications for activation of programmed cells.

Abstract

The immunoglobulin heavy-chain-associated tetrapeptide, tuftsin (Thr-Lys-Pro-Arg), known for its phagocytosis-stimulating activity, was found to augment the antigen-specific, macrophage-dependent education of T lymphocytes.The investigation of stereospecific characteristics of the tetrapeptide, by use of structural analogs with different modifications, revealed strict structural requirements for eliciting the immunogenic activity of macrophages. It was found that the most important moiety for its activity is the dipeptide ProArg. Ths finding is of interest in view of the appearance of this particular dipeptide in other bioregulatory peptides, including many of the peptide hormones. The significance of the appearance of a commoil structure in such molecules, which may act through specific receptors on different target cells, is discussed. Numerous studies have demonstrated the central role of T cells in humoral and cellular immune responses. In addition to functioning as effector cells, T cells may also augment as helpers or suppress the function of other cellular components of the immune system (1). The activation by antigen of T cells, resulting in antibody production, seems to depend on the presence of macrophages (2-5). The presentation of antigen via the macrophage determines the triggering and generation of an active T cell (4, 6). Yet, the mechanism that controls the activation of the immunogenic potential of the macrophages themselves is largely unknown.Studies of Najjar and his coworkers (7,8) and those carried out in our laboratory (9, 10) showed that the basic tetrapeptide

New biochemical marker for bone metabolism. Measurement by radioimmunoassay of bone GLA protein in the plasma of normal subjects and patients with bone disease.

“…A role for BGP in bone mineralization and structure appears to be unlikely because of the absence of detectable abnormalities in bones from vitamin K-deficient animals, which have been <5% of the normal BGP level (9). An informational or hormonal function for BGP is supported by sequence features (5) such as the two pairs of basic residues, which are proteolytic cleavage sites in the activation of proteins such as proinsulin (16) and the pro-lys unit, which is present in many informational proteins (17). Studies are also in progress to test possible informational functions for the BGP (9,(18)(19)(20).…”

Anti-tumour effect of the physiological tetrapeptide, tuftsin

“…In addition to human and dog PMNs, tuftsin has been shown to stimulate the phagocytic activity of guinea-pig peritoneal granulocytes, mouse peritoneal macrophages, and rabbit alveolar macrophages (Constantopoulos & Najjar, 1972). Tuftsin also enhances the reduction of nitrous blue tetrazolium by human PMNs (Spirer et al, 1975;Fridkin et al, 1977), the random migration of human mononuclear cells (Nishioka, 1976(Nishioka, , 1978 and antigen-specific macrophagedependent education of T lymphocytes (Tzehoval et al, 1978). Recently, the presence of specific binding sites for tuftsin on human PMNs and monocytes has also been revealed .…”

Klinische und physiologische aspekte von Tuftsin-Mangelsyndromen mit gest�rter Phagocytose

“…The reSults obtained in our laboratorY [4-9, 32-34, 38-40] by Martinez et al, [25,26] and Tzehoval et al [49] emphasize the highly specific nature of the functional activity of tuftsin. In fact, the very phagocytic cells that tuftsin stimulates, the blood neutrophils and body macrophages, alone of all blood cells show specific receptors to tuftsin [27,48].…”

“…Recently, it was clearly demonstrated in Feldman's laboratory that tuftsin, at an incredibly small concentration (16nM) stimulates considerably the immunogenic function of the macrophage [49]. This may well be a major and more distal function of tuftsin.…”