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Interleukin-6 mediates PSAT1 expression and serine metabolism in TSC2-deficient cells

Ji Wang1, Harilaos Filippakis1, Thomas Hougard1

  • 1Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.

Proceedings of the National Academy of Sciences of the United States of America
|September 21, 2021
PubMed

Insights

Interleukin-6 (IL-6) drives cell growth in Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) by regulating serine biosynthesis. Blocking IL-6 may offer a new therapeutic strategy for these mTORC1-driven diseases.

Area of Science:

  • Molecular Biology
  • Oncology
  • Metabolic Pathways

Background:

  • Tuberous Sclerosis Complex (TSC) and Lymphangioleiomyomatosis (LAM) are linked to hyperactive mechanistic Target of Rapamycin Complex 1 (mTORC1) signaling, often due to mutations in TSC1 or TSC2.
  • Previous studies indicate aberrant cellular processes in TSC2-deficient cells, but the specific molecular mechanisms driving disease pathology remain incompletely understood.

Purpose of the Study:

  • To investigate the role of cytokines, specifically Interleukin-6 (IL-6), in the pathogenesis of TSC and LAM.
  • To elucidate the functional impact of IL-6 on cellular metabolism and proliferation in TSC2-deficient cells.
  • To explore the therapeutic potential of targeting IL-6 in TSC and LAM models.

Main Methods:

  • Cytokine profiling of patient-derived TSC2-deficient LAM cells.
  • Measurement of IL-6 levels in patient plasma and cell secretions.
  • In vitro studies involving IL-6 blockade (antibody treatment) and IL-6 knockout cells.
  • Analysis of cellular proliferation, migration, oxygen consumption, and extracellular acidification.
  • U-13C glucose tracing to assess serine metabolism and phosphoserine aminotransferase 1 (PSAT1) expression.
  • In vivo studies using a mouse model of TSC2-deficiency treated with anti-IL-6 antibody.

Main Results:

  • Elevated IL-6 transcription and secretion were observed in TSC2-deficient LAM cells and plasma compared to controls.
  • IL-6 blockade significantly inhibited proliferation, migration, and altered metabolic activity (oxygen consumption, extracellular acidification) of TSC2-deficient cells.
  • IL-6 was found to regulate de novo serine biosynthesis by modulating PSAT1 expression, and IL-6 blockade reduced renal tumor growth in vivo.

Conclusions:

  • Interleukin-6 plays a critical role in promoting proliferation and altering metabolism in TSC2-deficient cells, partly through regulating serine biosynthesis.
  • Targeting IL-6 represents a promising therapeutic strategy for tumors associated with mTORC1 hyperactivity, including those in TSC and LAM.
  • This study reveals a novel IL-6-dependent pathway impacting serine metabolism relevant to TSC and LAM pathogenesis.
Keywords:
interleukin 6lymphangioleiomyomatosismTORC1phosphoserine aminotransferase 1 (PSAT1)tuberous sclerosis complex

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