Regulation of the Acute Phase Response by Cytokines

REGULATION OF THE ACUTE PHASE RESPONSE BY CYTOKINES IRVING KUSHNER* Abbreviations C-I INHC-I inhibitor CRPC-reactive protein INF7interferon ? IL-Iinterleukin-1 IL-6interleukin-6 IL-Ilinterleukin-11 LIFleukemia inhibitory factor SAAserum amyloid A TGFßtransforming growth factor ß TNFtumor necrosis factor The Acute Phase Response During good health, when there are no substantial threats to body integrity, our homeostatic mechanisms maintain an optimal internal environment in the face of a constantly changing external environment. Following a wide variety of noxious stimuli, however, the local inflammatory response is accompanied by a large number of systemic and metabolic changes, referred to collectively as the acute phase response, which represent the substitution of new "set points" for those which normally maintain internal stability [I]. The acute phase response is presumed to play a major adaptive and defense role; in the face of Supported in part by NIH grant AG 02467. The author expresses gratitude to Nancy Kessler for her secretarial assistance and to Debra Rzewnicki for her technical assistance. *Professor of medicine and pathology, Case Western Reserve University, MetroHealth Medical Center, Cleveland, Ohio 44109-1998.© 1993 by The University of Chicago. All rights reserved. 003 1-5982/93/3604-0824$0 1 .00 Perspectives in Biology and Medicine, 36, 4 ¦ Summer 1993 611 significant tissue injury and infection, defense mechanisms must take priority over normal homeostatic states. Stimuli that commonly give rise to the acute phase response include bacterial infection, surgical or other trauma, neoplasms, burn injury, tissue infarction, various immunologically mediated and crystal-induced inflammatory states, and childbirth. Among the changes in homeostatic settings described during the acute phase response are fever, altered synthesis of a number of endocrine hormones, alterations in plasma cation concentrations, altered hematopoiesis, inhibition of bone formation , negative nitrogen balance (largely resulting from proteolysis and decreased protein synthesis in skeletal muscle) with consequent gluconeogenesis , and alterations in lipid metabolism. The acute phase response may be relatively transient, reverting to normal with recovery, or it can be persistent in chronic disease. In a narrower and more frequently employed sense, the term acute phase response refers to changes in concentrations of a large number of plasma proteins, which reflect reorchestration of the pattern of gene expression of secretory proteins in hepatocytes. Both increases and decreases in synthesis are seen; changes in different proteins occur at differing rates and to different degrees. In man, synthesis of albumin, transthyretin, transferrin, alphafetoprotein, and a-2 HS glycoprotein, the "negative" acute phase proteins, characteristically diminishes. Ceruloplasmin and the complement components C3 and C4 display only modest "positive" acute phase behavior (typically about 50% elevation), while concentrations of a number of proteins including haptoglobin, a-I protease inhibitor, a-I antichymotrypsin, and fibrinogen regularly increase two- to five-fold or more. CRP (C-reactive protein) and SAA (serum amyloid A) are the two major human acute phase proteins. Both are normally present in plasma in only trace amounts, but dramatic increases in their rates of synthesis and consequent plasma concentrations may occur following stimulus; levels more than 1,000-fold greater than normal are seen in some severely infected individuals. Other less well-studied positive human acute phase proteins include, among others , several complement components (including C-I inhibitor), ferritin, and plasminogen activator inhibitor type-1. In general, rapidity of change of plasma protein concentrations parallels magnitude of change. The functional roles of many of the human acute phase proteins can reasonably be inferred from their known functions [reviewed in 2]. A number of acute phase proteins, including the complement components , fibrinogen, and CRP, can influence the inflammatory and tissue repair processes. Haptoglobin, hemopexin, and ceruloplasmin all play antioxidant roles and can be presumed to modulate the inflammatory process, as can the antiproteases ct-1 protease inhibitor, ct-1 antichymotrypsin , and C-I inhibitor. Recently, haptoglobin has also been shown 612 Irving Kushner ¦ The Acute Phase Response to stimulate angiogenesis. In addition to these local effects, a number of acute phase changes, such as fever, hypercortisolemia, and hypoferremia , are felt to provide a systemic environment more suited to the defensive and adaptive requirements of coping with significant tissue injury or infection than that which normally exists. Regulation ofAcute Phase Protein Synthesis Role of Cytokines...