High-dose growth hormone does not affect proinflammatory cytokine (tumor necrosis factor-alpha, interleukin-6, and interferon-gamma) release from activated peripheral blood mononuclear cells or after minimal to moderate surgical stress

High-dose GH therapy, with GH doses 10-20 times the normal replacement dose for GH-deficient adults, has been used as an anti-catabolic agent in a num ber of different patient groups. A recent study, however, has shown an incr ease in mortality in critically ill patients treated with high-dose GH. The increased mortality was associated with multiorgan failure, septic shock, and uncontrolled infection, suggesting that GH may have altered the immune response. The GH receptor and GH are both expressed in peripheral blood mon onuclear cells (PBMCs); thus, GH could act as either an endocrine or an aut ocrine modulator of the immune response. We have examined the hypothesis th at high-dose GH therapy may induce proinflammatory cytokines, which are imp licated in septic shock. To do this we measured cytokine production by PBMC s incubated in conditions that simulated high-dose GH therapy, and we measu red cytokine levels in patients undergoing laparoscopic cholecystectomy who were randomized to receive either high-dose GH therapy (13 IU/m(2) day) or placebo. To confirm the biological activity of GH in our cell culture system we used a Stat5 functional assay. In this assay GH induced a bell-shaped curve, wi th a maximal response at GH levels between 100-1000 ng/mL. PBMCs from healt hy volunteers were incubated with GH in doses from 1-1000 ng/mL for 6-72 h under resting conditions and after activation with endotoxin and the mixed lymphocyte reaction. Studies were repeated with PBMCs from six individuals using a GH dose of 100 ng/mL (the level of GH found after high-dose GH ther apy) and an endotoxin dose that gave a submaximal response (0.01 ng/mL). GH had no effect on cell proliferation or the production of tumor necrosis fa ctor-alpha (TNF-alpha), interleukin-6 (IL-6), or interferon-gamma (IFN gamm a). In patients undergoing laparoscopic cholecystectomy there was a time-re lated effect of surgery on cytokine levels. There was a rise in IL-6 and a fall in TNF alpha at 24 h after surgery; however, high-dose GH therapy had no effect on the cytokine response. We considered the possibility that endo genous GH production by PBMCs could influence the cytokine response in acti vated PBMCs; however, incubation of PBMCs in the presence of the GH recepto r antagonist, B2036, had no effect on TNF alpha, IL-6, or IFN gamma product ion by PBMCs in either the mixed lymphocyte reaction or when activated by e ndotoxin. These results suggest that high-dose GH therapy does not alter the proinfla mmatory cytokine response to surgery or endotorrin. The results do not excl ude an effect of GH on the immune response, but they suggest that the morta lity seen in critically ill patients may be due to factors other than immun e modulation.