The concept of the four cardinal signs of acute inflammation comes from 
antiquity as rubor et tumor cum calore et dolore, (redness and swelling with 
heat and pain) extended later by functio laesa (loss of function). The 
contemporary understanding of this process we owe to 19th-century milestone 
discoveries by Rudolph Virchow, Julius Cohnheim and Elie Metchnikoff. In the 
20th century, the development of potent technological tools allowed the rapid 
expansion of knowledge of the cells and mediators of inflammatory processes, as 
well as the molecular mechanisms of their interactions. It turned out that some 
mediators of inflammation have both local and distant targets, among them the 
liver (responding by the production of several acute phase reactants) and 
neurohormonal centers. In the last decades it has become clear that the immune 
system shares mediators and their receptors with the neurohormonal system of the 
body; thus, they form a common homeostatic entity. Such an integrative view, 
introduced by J. Edwin Blalock, when combined with Hans Selye's concept of 
stress, led to the contemporary understanding of sickness behavior, defined by 
Robert Dantzer as a highly organized strategy of the organism to fight 
infections and to respond to other environmental stressors.