NF-kB and AP-1 Molecular Signaling Mechanisms of Intrinsic And Extrinsic Skin Aging

The molecular signaling pathways associated with skin aging is most and initially studied in the photo skin aging. Numerous researches published combined the pieces of discovery into an general overview picture about what occurred molecularly in photo skin aging. It is generally believed the molecular and cellular changes associated with chronological skin aging is basically parallel those seen in photoaging, but are generally less severe. In addition, other environmental stressors may initiate molecular pathways very similar to those discovered in sun-exposed skin. Multiple cascades of signal transduction pathways involved in the intrinsic and extrinsic aging generally converge into the regulation and activation of two transcription factors – NF-kB and AP-1. NF-kB regulate and activate genes in immune response and is involved in what is know as inflammaging while AP-1 regulate and activate genes that result in the increased extracellular matrix fiber network degradation (collagen breakdown) and decreases the production of new collagen.

UV irradiation of skin in vivo results first in increased levels of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) in skin. Excesses of ROS, which result from aerobic metabolism, accumulate over time during chronological aging as well. H2O2 can be converted to the reactive hydroxyl radical. ROS triggers various signal transduction pathways through activating membrane bound receptors (receptor tyrosine kinases, RTK) for various cytokines (IL-1) and growth factors (EGF, IKGF, TNF-a).which further activate the downstream mitogen-activated protein MAP Kinase signal transduction pathways – a common route shared by many inducers/signals. Receptor activation is mediated in part through ROS-induced inactivation of tyrosine phosphatase whose function is to keep receptors dephosphorylated in an inactive form. For example, under physiological conditions, the EGF receptor exists in an inactive state with low phosphorylation because of its tyrosine phosphatases subunit which removes any phosphates. The hydroxyl radical oxidizes tyrosine phosphatase, rendering it inactive, thus thereby resulting in a constitutively active EGF receptor. The EGF receptor becomes activated within 15 minutes of UV exposure in human skin in vivo and remains activated for at least two hours.

Receptor (i.e. Receptor tyrosine kinases, RTK) activation leads to intracellular signaling (MAP) kinases pathway. There are three classic MAP kinase pathways – ERK (activated by extracellular signal), JNK and p38. UV irradiation activates all three pathways in skin in vivo. The primary end effector of all three MAP kinase pathways is the increased level of transcription factor activator protein-1 (AP-1). The activated AP-1 regulates/activates transcription of several matrix metalloproteinases (MMPs). MMPs are able to degrade many extracellular matrix proteins. Several MMPs are upregulated by AP-1. These include: MMP-1 (collagenase 1), which breaks down types I and III collagen; MMP-9 (gelatinase B), which further breaks down the collagen fragments produced by collagenase; and MMP-3 (stromelysin1), which also degrades collagen. In human skin in vivo, expression of these three MMPs is induced by UV irradiation. This activation of MMPs result in increased collagen breakdown, which has been shown within 24 hours of UV irradiation in vivo. In addition, AP-1 also inhibits collagen synthesis by negatively regulating transcription of type I procollagen genes. mRNA and protein expression of type I procollagen are decreased within eight hours of UV irradiation of human skin in vivo, and become almost absent in the upper dermis within 24 hours of UV irradiation. In addition to receptor activation, ceramide released from the damaged cellular membrane by ROS also activates AP-1 signaling pathway.

UV irradiation enhance collagen degradation and down regulate collagen synthesis not only via the EGF receptor pathway and AP-1 activation. It also block the transforming growth factor-beta (TGF-β) signaling pathway. In skin, TGF-β and TGF-β signaling pathway induces synthesis and secretion of both collagen (collagens I and III) and elastin; and negatively regulates keratinocyte proliferation. TGF-β signaling pathway also downregulate MMPs genes that break down collagen, including MMP-1 and MMP-3. TGF-β exerts its action by binding to its cell surface receptor complex, which is typically composed of TGF-β receptor proteins type I (TβRI) and II (TβRII). When TGF-β binds to TβRII within this complex, it activates the intrinsic serine–threonine kinase activity of TβRI and cascades of signal transduction result in phosphorylation and activation of transcription factors Smad2 and Smad3, which can then combine with Smad4, translocate into the nucleus and regulate/activate genes, including type I collagen. UV irradiation results in downregulation of TβRII gene within eight hours. The decrease or inactivation of TβRII blocks downstream signaling pathways for subsequent activation of type I procollagen. UV irradiation also induces expression of Smad7, which inactivates Smad2 and Smad3. Both TβRII downregulation and Smad7 activation by UV is actually mediated by AP-1; therefore, AP-1 has the direct effect of inducing MMPs, and also has the indirect effect of decrease collagen production through activating Smad7 and/or decreasing TβRII. In addition, inactivation of TGF-β signaling pathway triggers keratinocyte proliferation and epidermal hyperplasia

In addition to activating MAP kinase signaling pathway, receptor tyrosine kinases RTK (activated by ROS as has been mentioned) also activate phosphoinositide3-kinase (PI-3 kinase) signal transduction pathway. Akt/PHEN is the downstream effector of PI-3 kinase pathway where Akt, a kinase is activated and PTEN is inactivated. AKt may activate and regulate AP-1 activity which in turn activate MMPs. PI-3 kinase/Akt pathway has been identified as the effectors of cell survival and proliferation in many cell types. UV induced PI-3/Akt pathway can activate genes in stimulating cellular proliferation.

Photoaged skin is also characterized by an approximately 50% reduction in functional intact collagen while fragmented collagen is increased by about four-fold. The damaged fragmented collagen fiber network further exacerbates the procollagen synthesis by fibroblast. The fragmented collagen surrounding the fibroblast changed mechanical and isometric tension of fibroblast in all directions. fibroblast develops a collapsed and elongated shape. the fibroblast is unable to function appropriately so that procollagen synthesis is decreased. Once initiated, this cycle of degradation of collagen decreased procollagen synthesis is the primary structural basis for the aging skin phenotypes. AP-1 activity is also increased in intrinsic aging process, as are levels of MMP-1 and MMP-9 and levels of degraded collagen. Type I procollagen synthesis is also reduced.

UV irradiation and ROS also activate transcription factor NF-kB. NF-kB are involved mainly in stress-induced, immune, and inflammatory responses and therefore is significant in inflammaging mechanism. UV irradiation and ROS triggered NF-kB activation is also mediated and transduced through MAP kinase pathway (see post “Is NF-kB the Secret to Skin Aging?”). NF-kB signaling activate/regulate proinflammatory cytokines IL-1, IL-6, vascular endothelial growth factor (VEGF) and TNF-b, proteins involved in immunoregulation, and inflammaging mediator COX-2, inducible NO synthase (iNOS). Most proinflammatory cytokines are themselves activators of NF-kB signal transduction pathway upon binding to the corresponding cell surface receptors, thereby forming a positive loop accelerating the activation of genes regulated by NF-kB. NF-kB and/or NF-kB induced proinflammatory molecules stimulates MMPs as well, but primarily is MMP-8. MMP-8 is a collagenase of neutrophil origin, following neutrophil infiltration into UV-irradiated skin. Studies suggest that the main source for UV-induced secretion of MMPs and elastase are infiltrating cutaneous neutrophils.

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