Stefanie N. Vogel

The role of macrophages in the acute-phase response: SAA inducer is closely related to lymphocyte activating factor and endogenous pyrogen

Abstract An increase in the concentration of the acute-phase reactant, serum amyloid A (SAA), following endotoxin treatment, is a consequence of the action of lipopolysaccharide (LPS) on macrophages to produce a monokine, the SAA inducer, which in turn, triggers SAA synthesis by hepatocytes. We have found that murine SAA inducer is closely related, if not identical, to murine lymphocyte activating factor (LAF), otherwise known as Interleukin 1 (IL 1). Furthermore, both rabbit endogenous pryrogen (EP), which is believed to be identical to LAF (IL 1), and human LAF (IL 1), induced elevated SAA concentrations in C3H/HeJ mice. Antiserum previously shown to block both pyrogenic and thymocyte proliferating activities of the species of rabbit EP exhibiting an isoelectric point of pH 7.3 (EP 7), also blocked the SAA inducing activity of EP7. Phenylglyoxal treatment of highly purified murine LAF (IL 1) abrogated both thymocyte proliferating activity and the SAA inducing activity. These studies support and extend previous reports suggesting that within 2 hr of an inflammatory stimulus, macrophages produce a monokine that acts systemically to alter body temperature, activate T cells, and induce hepatic protein synthesis of acute-phase reactants.

BCG-induced enhancement of endotoxin sensitivity in C3H/HeJ mice. II. T cell modulation of macrophage sensitivity to LPS in vitro

Abstract BCG infection induces a marked increase in LPS sensitivity in vivo and will render genetically defective, LPS hyporesponsive, C3H/HeJ mice almost as sensitive to LPS as normal mice. In this study, we have examined the endotoxin sensitivity of lymphocytes and macrophages from BCG infected mice in order to determine the cellular basis of this effect. We have found that the alteration in endotoxin sensitivity is mediated by a primary effect of BCG infection on T lymphocytes rather than on macrophages. Macrophages from «LPS sensitive», BCG-infected C3H/HeJ mice remain unresponsive to LPS when tested in vitro . However, when peritoneal T lymphocytes from these LPS »corrected» mice were cocultured with LPS unresponsive C3H/HeJ macrophages, a conversion to the LPS-responsive state was observed as manifested by the ability of the macrophages to produce LAF (IL 1) upon LPS stimulation. T cells from normally LPS-responsive or BCG-infected C3H/HeN mice, but not from control C3H/HeJ mice, were also able to render C3H/HeJ macrophages sensitive to LPS. This activity was not affected by treatment of the column-purified T cells with anti-macrophage serum plus complement, indicating that the response was not due to residual LPS-responsive macrophages contaminating the T cell preparations. The ability of the T cell suspension to render C3H/HeJ macrophages capable of producing LAF (IL 1) in response to LPS was abrogated by treatment of the T cell preparations with anti-Thy 1.2 plus complement. These findings establish the importance of T lymphocytes in regulating the LPS sensitivity of macrophages in BCG infected C3H/HeJ mice and support the concept that macrophage LPS responsiveness is dependent upon a certain state of macrophage activation which is regulated by lymphocytes.

Inherent Macrophage Defects in Mice

Macrophages represent a highly diverse population of “phagocytic monocytes,” capable of effecting a number of important biological functions. The ubiquitous nature of macrophages as a network of circulating and fixed scavengers within the tissues, combined with their complex phagocytic and detoxifying abilities, subserve their role as the primary host surveillance system. One major function of macrophages is to protect the host from harmful infectious agents, particularly in the early phases of infection, prior to the establishment of a specific immune response. To this end, highly differentiated or “activated” macrophages (Mackaness, 1969) are capable of killing intracellular parasites and tumor cells. In addition to the ability to deal directly with invading microorganisms, the macrophage has been shown to be the source of a number of “monokines” (substances synthesized by macrophages) such as lymphocyte-activating factor, prostaglandins, and certain complement components, each of which modulates the immune response. Moreover, macrophages have clearly been implicated as an essential accessory cell in the establishment of antigen-specific immune responses, and in some cases may act to suppress both humoral and cellular immune functions.

The Effects of Endotoxin on Macrophages and T-Lymphocytes

The immune response is generated by a complex series of interactions between three major lymphoreticular cell types, macrophages and B and T lymphocytes (Fig. 1). This response is initiated by the interaction of an external stimulus, such as an antigen or mitogen, with each of all of these cells. The initial stimulation also results in the production of a number of soluble intercellular messengers i.e., lymphokines or monokines, that act within the system to produce a marked amplification of the response.