Interleukin-1 and Transforming Growth Factor Beta: Commonly Opposing, but Sometimes Supporting, Master Regulators of the Corneal Wound Healing Response to Injury

Abstract

Purpose Interleukin (IL)-1α/IL-1β and transforming growth factor (TGF)β1/TGFβ2 have both been promoted as “master regulators” of the corneal wound healing response due to the large number of processes each regulates after injury or infection. The purpose of this review is to highlight the interactions between these systems in regulating corneal wound healing. Methods We conducted a systematic review of the literature. Results Both regulator pairs bind to receptors expressed on keratocytes, corneal fibroblasts, and myofibroblasts, as well as bone marrow-derived cells that include fibrocytes. IL-1α and IL-1β modulate healing functions, such as keratocyte apoptosis, chemokine production by corneal fibroblasts, hepatocyte growth factor (HGF), and keratinocyte growth factor (KGF) production by keratocytes and corneal fibroblasts, expression of metalloproteinases and collagenases by corneal fibroblasts, and myofibroblast apoptosis. TGFβ1 and TGFβ2 stimulate the development of myofibroblasts from keratocyte and fibrocyte progenitor cells, and adequate stromal levels are requisite for the persistence of myofibroblasts. Conversely, TGFβ3, although it functions via the same TGF beta I and II receptors, may, at least in some circumstances, play a more antifibrotic role—although it also upregulates the expression of many profibrotic genes. Conclusions The overall effects of these two growth factor-cytokine-receptor systems in controlling the corneal wound healing response must be coordinated during the wound healing response to injury or infection. The activities of both systems must be downregulated in coordinated fashion to terminate the response to injury and eliminate fibrosis. Translational Relevance A better standing of the IL-1 and TGFβ systems will likely lead to better approaches to control the excessive healing response to infections and injuries leading to scarring corneal fibrosis.

miR-218-5p Induces Interleukin-1β and Endovascular Trophoblast Differentiation by Targeting the Transforming Growth Factor β-SMAD2 Pathway

“…In mouse calvarial osteoblasts, TGFβ abolishes the induction of cyclooxygenase 2 by IL1β ( 67 ). TGFβ and IL1β also antagonistically modulate apoptosis of corneal myoblasts ( 68 ). In trophoblasts, TGFβ and IL1β have inhibitory and stimulatory effects, respectively, on cell invasion ( 32 , 69 , 70 ).…”

The NLRP3 Activation in Infiltrating Macrophages Contributes to Corneal Fibrosis by Inducing TGF-β1 Expression in the Corneal Epithelium

“…Emerging evidence has demonstrated that the activation of the NLRP3 inflammasome involves an inflammatory response, which is mainly driven by the release of proinflammatory cytokine IL-1β and IL-18. 29 , 30 Coincidentally, IL-1β plays a pivotal role in the pathogenesis of inflammation and fibrosis 31 , 32 ; moreover, it amplifies the effects of other cytokines. 18 In liver diseases, the NLRP3 inflammasome activation indirectly induces liver inflammation and fibrosis in a cytokine-dependent manner.…”

Corneal Opacity: Cell Biological Determinants of the Transition From Transparency to Transient Haze to Scarring Fibrosis, and Resolution, After Injury

“…IL-1 alpha released by epithelial or endothelial injury triggers other important functions in corneal fibroblasts. 66 Gene array experiments 67 demonstrated that IL-1 alpha (and tumor necrosis factor-alpha) stimulate the transcription of many chemokines, such as monocyte-derived neutrophil chemotactic factor, chemokine (C–C motif) ligand 2, also called monocyte chemoattractant protein-1, granulocyte colony-stimulating factor, and C-X-C motif chemokine 5 (also called neutrophil-activating peptide or ENA-78), that amplify the effect of IL-1 alpha itself in drawing not only fibrocytes, but other bone marrow-derived cells, such as lymphocytes, neutrophils, and macrophages, into the corneal stroma. IL-1 alpha also upregulates the production of hepatocyte growth factor and keratinocyte growth factor (or fibroblast growth factor-7) 68 , 69 that stimulate epithelial healing by modulating the proliferation, motility, differentiation, and apoptosis of corneal epithelial cells.…”