title: 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.
abstract: 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 number of different patient groups. A recent study, however, has shown an increase 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 mononuclear cells (PBMCs); thus, GH could act as either an endocrine or an autocrine modulator of the immune response. We have examined the hypothesis that high-dose GH therapy may induce proinflammatory cytokines, which are implicated in septic shock. To do this we measured cytokine production by PBMCs incubated in conditions that simulated high-dose GH therapy, and we measured cytokine levels in patients undergoing laparoscopic cholecystectomy who were randomized to receive either high-dose GH therapy (13 IU/m2 x 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, with a maximal response at GH levels between 100-1,000 ng/mL. PBMCs from healthy volunteers were incubated with GH in doses from 1-1,000 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 therapy) 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 factor-alpha (TNFalpha), interleukin-6 (IL-6), or interferon-gamma (IFNgamma). In patients undergoing laparoscopic cholecystectomy there was a time-related effect of surgery on cytokine levels. There was a rise in IL-6 and a fall in TNFalpha at 24 h after surgery; however, high-dose GH therapy had no effect on the cytokine response. We considered the possibility that endogenous GH production by PBMCs could influence the cytokine response in activated PBMCs; however, incubation of PBMCs in the presence of the GH receptor antagonist, B2036, had no effect on TNFalpha, IL-6, or IFNgamma production by PBMCs in either the mixed lymphocyte reaction or when activated by endotoxin. These results suggest that high-dose GH therapy does not alter the proinflammatory cytokine response to surgery or endotoxin. The results do not exclude an effect of GH on the immune response, but they suggest that the mortality seen in critically ill patients may be due to factors other than immune modulation.
authors.affiliation: Division of Clinical Sciences and SCHARR, Sheffield University, United Kingdom.
authors.forename: S H
authors.initials: SH
authors.lastname: Zarkesh-Esfahani
authors.forename: O
authors.initials: O
authors.lastname: Kolstad
authors.forename: R A
authors.initials: RA
authors.lastname: Metcalfe
authors.forename: P F
authors.initials: PF
authors.lastname: Watson
authors.forename: S
authors.initials: S
authors.lastname: von Laue
authors.forename: S
authors.initials: S
authors.lastname: Walters
authors.forename: A
authors.initials: A
authors.lastname: Revhaug
authors.forename: A P
authors.initials: AP
authors.lastname: Weetman
authors.forename: R J
authors.initials: RJ
authors.lastname: Ross
mesh_terms: D000328:Adult; D000368:Aged; D002763:Cholecystectomy; D016207:Cytokines / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics; D004731:Endotoxins / Q000494:pharmacology; D013006:Growth Hormone / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D008070:Lipopolysaccharides / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008894:Milk Proteins; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D050799:STAT5 Transcription Factor; D013312:Stress, Physiological / Q000378:metabolism*; D013514:Surgical Procedures, Operative / Q000009:adverse effects*; D015534:Trans-Activators / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D016207:Cytokines; D004268:DNA-Binding Proteins; D004731:Endotoxins; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008894:Milk Proteins; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D013006:Growth Hormone; D008156:Luciferases