Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages

Our plain-English summary of Hyaluronate activation of CD44 induces insulin-like growth factor-1 expression by a tumor necrosis factor-alpha-dependent mechanism in murine macrophages, by P.W. Noble, F.R. Lake, P.M. Henson, et al (The Journal of Clinical Investigation, 1993).

The study

• Authors: P.W. Noble, F.R. Lake, P.M. Henson, D.W. Riches
• Journal: The Journal of Clinical Investigation
• Published: 1993;91(6):2368-77
• Cited by: 297 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Macrophages participate in inflammatory and repair processes in part through the selective release of cytokines that contribute to tissue remodeling. Extracellular matrix components generated at inflammatory sites may influence tissue remodeling by effects on leukocyte adherence and local cytokine production. In murine bone marrow-derived macrophages, we found that soluble hyaluronic acid stimulated IL-1 beta, TNF alpha, and insulin-like growth factor-1 (IGF-1) mRNA transcript expression as well as IGF-1 protein synthesis. Monoclonal antibodies to the hyaluronic acid receptor CD44 blocked the effects of hyaluronic acid on IL-1 beta, TNF alpha, and IGF-1 expression. TNF alpha and IL-1 beta mRNA expression preceded IGF-1 protein synthesis, and TNF alpha, but not IL-1 beta, was found to directly stimulate IGF-1. Furthermore, IGF-1 induction was dependent on endogenous TNF alpha production since IGF-1 protein synthesis was inhibited in the presence of anti-TNF alpha antiserum. In addition, IL-1 beta was found to exert a regulatory role on IGF-1 production by enhancing the TNF alpha effect. IL-1 beta and TNF alpha mRNA transcript expression as well as IGF-1 protein synthesis were also stimulated by chrysotile asbestos. Anti-CD44 antibodies had no effect whereas anti-TNF alpha antiserum blocked asbestos-stimulated IGF-1 production. These results indicate that hyaluronate activation of CD44 induces cytokine expression and macrophage-derived IGF-1 production is dependent on TNF alpha expression.

In plain English

This was a laboratory study of macrophages, a type of immune cell, grown from the bone marrow of female C3H/HeJ mice. The authors exposed the cells to soluble hyaluronic acid, a component of the material between cells. They measured newly made insulin-like growth factor-1 (IGF-1) protein, plus messenger RNA for IGF-1 and for the signalling proteins TNF-alpha and IL-1 beta. Hyaluronic acid at 1 mg/ml increased IGF-1 protein synthesis fourfold and IGF-1 messenger RNA twofold. TNF-alpha and IL-1 beta messages rose earlier. Antibodies against CD44, the hyaluronic acid receptor, blocked the rise in IGF-1 protein synthesis and in TNF-alpha and IL-1 beta messages. Added TNF-alpha stimulated IGF-1. IL-1 beta alone had no significant effect but enhanced the TNF-alpha effect. Blocking TNF-alpha prevented the hyaluronic acid-induced rise in IGF-1. Chrysotile asbestos also raised IL-1 beta and TNF-alpha messages. At 50 micrograms per ml for 18 hours it raised IGF-1 synthesis, though less than hyaluronic acid did. Blocking TNF-alpha prevented the asbestos effect, but CD44 antibodies did not. The authors concluded that the two substances appear to act through distinct cell-surface mechanisms but share a common pathway of inducing TNF-alpha production.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) experiment on cultured mouse bone marrow-derived macrophages
• Who was studied: Macrophages grown from bone marrow of female C3H/HeJ mice, 8 weeks old, obtained from The Jackson Laboratory. The number of mice is not stated.
• Exposure: Soluble hyaluronic acid (1 microgram/ml to 1 mg/ml) and related glycosaminoglycans (heparan sulfate, heparin, chondroitin sulfate A). Also added TNF-alpha and IL-1 beta, and chrysotile asbestos at 50 micrograms/ml. Exposures were given with or without anti-CD44 antibodies or anti-TNF-alpha or anti-IL-1 beta antisera.
• Main results:
  • In macrophages exposed to hyaluronic acid, IGF-1 protein synthesis increased fourfold at 1 mg/ml.
  • In macrophages exposed to 1 mg/ml hyaluronic acid, IGF-1 messenger RNA increased twofold at 12 hours.
  • In hyaluronic acid-exposed macrophages, TNF-alpha messenger RNA was strongly induced at 1 hour, earlier than the rise in IGF-1.
  • Heparan sulfate, heparin and chondroitin sulfate A at 1 mg/ml did not significantly increase IGF-1 protein synthesis.
  • In hyaluronic acid-exposed macrophages, anti-CD44 antibodies (KM 201) blocked IGF-1 protein synthesis. Pooled rat IgG did not.
  • In hyaluronic acid-exposed macrophages, anti-CD44 antibodies (KM 201) inhibited IL-1 beta and TNF-alpha messenger RNA expression.
  • Added TNF-alpha stimulated IGF-1 synthesis in macrophages, while IL-1 beta alone had no significant effect.
  • Added TNF-alpha at 10 ng/ml produced nearly a sixfold increase in IGF-1 synthesis in macrophages.
  • Pretreating macrophages with IL-1 beta enhanced the effect of TNF-alpha on IGF-1 synthesis.
  • Anti-TNF-alpha antiserum, but not anti-IL-1 beta antiserum, inhibited hyaluronic acid-stimulated IGF-1 synthesis. The authors judged endogenous TNF-alpha critical.
  • Chrysotile asbestos stimulated IL-1 beta, TNF-alpha and IGF-1 in macrophages, as hyaluronic acid did.
  • The increase in IGF-1 synthesis with chrysotile asbestos was smaller than with hyaluronic acid.
  • In asbestos-exposed macrophages, anti-TNF-alpha antiserum blocked IGF-1 protein synthesis.
  • In asbestos-exposed macrophages, anti-CD44 antibodies (KM 201) had no effect on IGF-1 synthesis.
• The authors' conclusion: The authors concluded that hyaluronic acid stimulates macrophage IGF-1 by activating CD44 through a pathway requiring TNF-alpha. They also concluded that hyaluronic acid and chrysotile asbestos appear to use distinct cell-surface mechanisms but share the step of inducing TNF-alpha production.

Topics

Medical terms in this study, explained in our Lexicon: Tumor Necrosis Factor-alpha (TNF-α), Macrophage, Cytokine, Hyaluronic Acid, Monoclonal, Chrysotile.

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