Endotoxin-Induced Proteolytic Reduction in Hepatic Growth Hormone (GH) Receptor: A Novel Mechanism for GH Insensitivity

Abstract

GH is an important anabolic hormone. We previously demonstrated in cell culture that the cell surface GH receptor (GHR) is susceptible to inducible metalloproteolytic cleavage that yields the shed receptor extracellular domain (called GH binding protein) and renders the cells desensitized to subsequent GH stimulation. Sepsis and inflammatory states are associated with hepatic desensitization to GH, although disparate mechanisms have been postulated in various animal models. Using C3H/HeJ mice, we now demonstrate that administration of lipopolysaccharide (LPS) causes marked hepatic desensitization to GH, assessed by monitoring signal transducer and activator of transcription 5 tyrosine phosphorylation and nuclear accumulation and with a novel noninvasive bioluminescence imaging system to track in vivo hepatic GH signaling serially in individual mice. This endotoxin-induced desensitization was accompanied by marked loss of hepatic GHR, which was not explained by changes in GHR mRNA abundance. Furthermore, we observe that LPS causes GH-binding protein shedding of a hepatically expressed wild-type GHR but not a GHR with a mutation in the metalloprotease cleavage site. These data suggest that in this model system, LPS-induced desensitization to GH is associated with proteolytic GHR cleavage. These data are the first to demonstrate inducible in vivo GHR proteolysis and suggest this is a mechanism to regulate GH sensitivity and its anabolic effects during sepsis or inflammation.

Mechanisms of growth impairment in pediatric Crohn's disease

“…information from both animal models and human studies supports each of these potential mechanisms ( Figure 3). 14,15,49,50,[52][53][54][55][56][57][58][59][60][61][62][63][64] IGF-I-independent mechanisms inflammatory cytokines inhibit linear growth through pathways other than iGFi production. animal experi ments have shown that tnF and il1 increase chondro cyte death and thus may have a deleterious effect on growth.…”

“…54 Both mechanisms are seemingly independent of the inflammatory cytokine cascade, and the addition of antitnF antibody failed to abrogate this effect. 52 although certainly intriguing, the clinical signifi cance of these findings and their rela tive importance as a mechanism in the setting of growth impairment and Crohn's disease is yet to be determined.…”

“…92 similarly, data from sawczenko et al demon strate a potential causal relationship between genetic variation in the promoter region for IL6, alterations in subsequent il6 expression and differ ential effects on linear growth impairment during (1) LPs reduces GH receptor density by inducing GH receptor proteolysis and shedding of GHBP . 52 (2) TNF downregulates GH receptor formation via inhibition of sp1 and sp3's ability to transactivate GHR. 53 iL-1 suppresses GHR promoter activity.…”

Lipopolysaccharide exposure is linked to activation of the acute phase response and growth failure in pediatric Crohnʼs disease and murine colitis

“…Aberrancy of the TLR signaling system may therefore regulate chronic inflammation in IBD. Moreover, our recent murine studies have shown that LPS can directly suppress growth hormone (GH) signaling, by inducing proteolytic degradation of the hepatic GH receptor (GHR) (18). LPS may therefore also contribute directly to linear growth failure in children with CD.…”

Comunicación bidireccional entre el sistema inmune y neuroendocrino a través de la hormona de crecimiento, prolactina y hepcidina

“…Sin embargo, a pesar de estos resultados, es posible que otros mecanismos sean los responsables de los cambios de GH inducido por LPS. Wang et al (28), en una investigación in vivo en ratones, reportaron que LPS inducen insensibilización de GH a través de la proteólisis de su receptor (GHR).…”