High-Dose Growth Hormone Does Not Affect Proinflammatory Cytokine (Tumor Necrosis Factor-α, Interleukin-6, and Interferon-γ) 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 anticatabolic 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/m 2 ⅐day) 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 bellshaped curve, with a maximal response at GH levels between 100-1000 ng/mL. PBMCs from healthy 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 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-␣ (TNF␣), interleukin-6 (IL-6), or interferon-␥ (IFN␥). 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 TNF␣ 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 TNF␣, IL-6, or IFN␥ 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. (J Clin Endocrinol Metab 85: 3383-3390, 2000)

IGF1 potentiates the pro-inflammatory response in human peripheral blood mononuclear cells via MAPK

“…In contrast to IGF1, stimulation of PBMCs with GH neither influences basal nor TLR ligand-induced cytokine production in PBMCs from healthy donors. While this is supported by some earlier research (Zarkesh-Esfahani et al 2000), others reported that GH increased the production of IFNg and IL1B in murine peritoneal macrophages (Sodhi & Tripathi 2008). Haeffner and coworkers report an inhibitory effect on TNF alpha secretion in monocytes and macrophages stimulated with both GH and LPS (Haeffner et al 1997).…”

Acromegaly, inflammation and cardiovascular disease: a review

“…However, in PBMC from healthy donors such an effect was not observed [145,148]. These conflicting results may be explained by the presence of a bell-shaped dose-response curve for GH [145]. The maximal effect on pro-inflammatory cytokine production has been observed with a dose of around 300 ng/ml in aforementioned studies.…”

“…Interestingly, increased production of TNF-α mRNA expression and secretion was observed in human monocytes and murine peritoneal macrophages after stimulation with IGF-1 in the same experimental setting [47]. In another study, ex vivo stimulation of human peripheral blood mononuclear cells (PBMCs) with 100 ng/ml GH, which was expected to elicit a maximal response, did not affect the production of TNF-α, IL-6 and IFN-γ, either in absence or presence of costimulation with the Toll-like Receptor (TLR)-ligand Lipopolysaccharide (LPS) [145]. However, co-stimulation with GH and LPS induced IL-6 and TNF-α expression and secretion in whole blood (WB) [146].…”

“…In addition, costimulation with LPS and GH inhibited TNF-α secretion in mononuclear cells [147]. However, in PBMC from healthy donors such an effect was not observed [145,148]. These conflicting results may be explained by the presence of a bell-shaped dose-response curve for GH [145].…”

“…several weeks) exposure to supraphysiological levels of GH results in increased inflammatory activity. On the contrary, exposure to physiological levels (which are aimed when treating GHD) or short-term exposure of non-GHD patients to supraphysiological GH dosages has neutral or antiinflammatory effects [50,67,145], which are suggested to be mediated via reduction of oxidative stress via induction of NO synthesis [67].…”