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Elevated cysteine-rich protein 61 (CCN1) promotes skin aging via upregulation of IL-1β in chronically sun-exposed human skin

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Abstract

Chronic exposure of human skin to solar ultraviolet (UV) irradiation causes premature skin aging, which is characterized by reduced type I collagen production and increased fragmentation of the dermal collagenous extracellular matrix. This imbalance of collagen homeostasis is mediated, in part, by elevated expression of the matricellular protein cysteine-rich protein 61 (CCN1), in dermal fibroblasts, the primary collagen producing cell type in human skin. Here, we report that the actions of CCN1 are mediated by induction of interleukin 1β (IL-1β). CCN1 and IL-1β are strikingly induced by acute UV irradiation, and constitutively elevated in sun-exposed prematurely aged human skin. Elevated CCN1 rapidly induces IL-1β, inhibits type I collagen production, and upregulates matrix metalloproteinase-1, which degrades collagen fibrils. Blockade of IL-1β actions by IL-1 receptor antagonist largely prevents the deleterious effects of CCN1 on collagen homeostasis. Furthermore, knockdown of CCN1 significantly reduces induction of IL-1β by UV irradiation, and thereby partially prevents collagen loss. These data demonstrate that elevated CCN1promotes inflammaging and collagen loss via induction of IL-1β and thereby contributes to the pathophysiology of premature aging in chronically sun-exposed human skin.

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Abbreviations

UV:

Ultraviolet

CCN1:

CCN family member 1

CCN family:

Cysteine-rich protein 61, connective tissue growth factor, nephroblastoma overexpressed

IL-1β:

Interleukin 1β

COL-1:

Type I collagen

MMP-1:

Matrix metalloproteinase-1

ECM:

Extracellular matrix

AFM:

Atomic force microscopy

AP-1:

Activator protein-1

NF-κB:

Nuclear factor kappa B

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Acknowledgments

We thank Suzan Rehbine for the procurement of tissue specimens, and Diane Fiolek and Patrick Robichaud for administrative assistance. This work was supported by the National Institute of Health (RO1 ES014697 and ES014697 30S1 to T. Quan).

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Authors and Affiliations

  1. Department of Dermatology, University of Michigan Medical School, 1301, E. Catherine, Medical Science I, Room 6447, Ann Arbor, MI, 48109-5609, USA

    Zhaoping Qin, Toru Okubo, John J. Voorhees, Gary J. Fisher & Taihao Quan

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  1. Zhaoping Qin
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  2. Toru Okubo
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  3. John J. Voorhees
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  4. Gary J. Fisher
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  5. Taihao Quan
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Correspondence to Taihao Quan.

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Qin, Z., Okubo, T., Voorhees, J.J. et al. Elevated cysteine-rich protein 61 (CCN1) promotes skin aging via upregulation of IL-1β in chronically sun-exposed human skin. AGE 36, 353–364 (2014). https://doi.org/10.1007/s11357-013-9565-4

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  • DOI: https://doi.org/10.1007/s11357-013-9565-4

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