Tumour necrosis factor production and natural killer cell activity in peripheral blood during treatment with recombinant tumour necrosis factor.

Tumour necrosis factor (TNF) has been found to be an important immunomodulator. Among other functions TNF activates natural killer (NK) cells and stimulates monocytes/macrophages in an autocrine fashion. TNF production and NK activity in peripheral blood mononuclear cells were determined in a clinical phase I study in which recombinant human (rh) TNF was administered as a continuous infusion weekly for a period of 8 weeks. Even though TNF production and NK activity were significantly reduced directly after rhTNF infusion the effect proved to be transient and most pronounced at the first rhTNF administration. One day after completion of the rhTNF infusion the peripheral cells released more TNF into the supernatant compared to TNF activity immediately before the rhTNF infusion. This effect was conspicuous in non-stimulated cultures. After repeated rhTNF infusions both stimulated and non-stimulated TNF production of the peripheral blood mononuclear cells was increased. NK cell activity was also enhanced after repeated cycles of rhTNF administration as compared to early rhTNF treatment. Thus, repeated rhTNF infusions lead to a stimulatory effect on TNF production and NK activity of peripheral blood cells

Mechanical and biochemical characterization of the contraction elicited by a calcium-independent myosin light chain kinase in chemically skinned smooth muscle

The contraction induced by a Ca2+-independent myosin light chain kinase (MLCK-) was characterized in terms of isometric force (Fo), immediate elastic recoil (SE), unloaded shortening velocity (Vus), shortening under a constant load and ATPase activity of chemically skinned smooth muscle preparations. These parameters were compared to those measured in a Ca2+-induced contraction to assess the nature of cross bridge interaction in the MLCK-induced contraction. Fo developed in chicken gizzard fibers as well as SE were similar in contractions elicited by either agent. Vus in the contraction induced by MLCK-(0.36 mg/ml) was similar though averaged 39.3±8.9% less than Vus induced by Ca2+ (1.6x10-6M) in the control fibers. Addition of Ca2+ (1.6x10-6M) to a contraction induced by MLCK-resulted in small increases in both Fo and Vus. Shortening under a constant load was similar for both types of contractions. The contraction induced by MLCK-was accompanied by an increased rate of ATP hydrolysis. The MLCK-induced contraction is thus kinetically similar though not identical to a contraction induced by Ca2+. We conclude that with respect to actin-myosin interaction, MLCK- and Ca2+-induced contractions are similar