Studies on the Pathogenesis of Fever

The metabolic reactions responsible for the release of endogenous pyrogen from rabbit granulocytes incubated in 0.15 M NaCl are specifically inhibited by the presence of K(+) (and by related alkali metal ions, Rb(+) and Cs(+)) in the medium. The inhibitory action of K(+) apparently involves penetration of the cell membrane and is directly antagonized by the cardiac glycoside, ouabain. It is concluded, therefore, that the inhibition of pyrogen release by extracellular K(+) is due to transport of K(+) into the cell. Although the precise molecular mechanisms which are responsible for the release of pyrogen from granulocytes incubated in K-free saline have not been elucidated, further study of the process has revealed: (a) that it is preceded by the accumulation of pyrogen within the cell, (b) that it depends upon the catalytic action of one or more sulfhydryl-containing enzymes, (c) that it does not require energy, either from glycolysis or from reactions depending on molecular oxygen, and (d) that its inhibition by K(+) and by arsenite is qualitatively similar to the depression caused by these same reagents on the release of other leucocytic proteins; i.e., lysozyme and aldolase.