Infrared A induced signal transduction

1. Abstract:

Background:
The relevance of IR radiation for premature skin ageing was described by L. Kligman over twenty years ago. It took 20 years until first insight into the mechanism of IR induced skin damage was obtained. We reported 2002 that low, physiologically relevant doses of IR-A in vitro lead to an induction of Matrixmetalloproteinase-1 (MMP-1). Matrixmetalloproteinases (MMPs) are zinc-dependent endopeptidases responsible for the degradation of extracellular matrix components such as collagen and elastin. In this project we study the signaling pathways which are involved in IRA-induced gene expression such as MMP-1.

Results:

IRA was found to act via a disturbance of the mitochondrial electron transport chain (mtETC). This multiprotein facility, driven by reduction equivalents (NADH/H+ and FADH2), is responsible for energy conservation by transferring electrons to oxygen while building up an electrochemical proton gradient across the inner mitochondrial membrane which in turn fuels the production of ATP from ADP and Pi. As this process is not error free, relatively small amounts of ROS are always generated. Upon IRA irradiation this amount is significantly increased (Schroeder et al., 2008a).

ROS are often recognized only as damaging agent, but they are well known to function in terms of cellular signaling. Reactive oxygen species (ROS) can serve to trigger molecular signaling responses and several studies indicate that ROS cause an inactivation of protein-tyrosine phosphatases (PTPs) by oxidizing conserved cysteine residues in the active sites of PTPs and thereby lead to a net increase in kinase phosphorylation/activation (Cross and Templeton, 2006).

After IRA irradiation not only the mitochondrial but the cellular ROS levels are increased and a disturbance of the cellular glutathione (GSH) equilibrium was observed (Schroeder et al., 2007). GSH is one of the most important endogenous antioxidants, it can prevent or repair oxidative damage, and as a consequence it is oxidized itself, forming the glutathione dimer (GSSG). In this regard, IRA irradiation leads to a significant shift of the GSH/GSSG equilibrium towards the oxidized form (Schroeder et al., 2007).

IRA-induced ROS production is not just a byproduct of the irradiation but of functional relevance because boosting the cellular antioxidative defense by increasing the cellular GSH content abrogated the IRA induced upregulation of MMP-1 (Schroeder et al., 2007). In addition, use of specific antioxidants in cell culture has also been shown to decrease the IRA induced effects (Schroeder et al., 2008b).

Mitochondria are known to act as a hub for cellular signaling with disruption of the mtETC being a prominent inducer of such retrograde (i.e. from mitochondria to nucleus) signaling. In contrast to anterograde signaling processes here the nuclear gene expression is regulated by events originating in the mitochondria. The IRA-induced increase in mitochondrial ROS was recently found to initiate such a retrograde signaling cascade.

Downstream of mitochondrial ROS, the IRA radiation induced signaling pathway relevant for MMP-1 induction has been found to involve the activation of MAPKinases with a prominent role of the extracellular regulated kinases 1 & 2 (ERK1/2).

In addition we were able to demonstrate the relevance of IRA-induced ROS production and MMP-1 expression in vivo in human skin (Schroeder et al 2008b).

Goals for 2009/10

Our recent and ongoing research activities target the retrograde signaling pathways initiated by IRA. Especially the involvement of the second messenger calcium in the cellular response to IRA will be investigated.

Publikations belonging to the topics

1. Peter Schroeder, Ines Hertel, Maren Schneider and Jean Krutmann; The effect of processed water on constitutive and ultraviolet A radiation induced level of mitochondrial DNA mutations in human dermal fibroblasts; Skin Pharmacol Physiol 2007; 20(2):116-119

2. Ellen Fritsche, Claudia Schäfer, Thomas Bernsmann, Christian Calles, Thorsten Bernshausen, Melanie Wurm, Y. Hashimiraga, Ulrike Hübenthal, Jason E. Cline, Peter Schroeder, Agneta Rannug; Lars-Oliver Klotz, P. Fürst, Helmut Hanenberg, Josef Abel and Jean Krutmann; Lightening up the UV response by identification of the Arylhydrocarbon Receptor as a cytoplasmatic target for Ultraviolet B radiation. PNAS 2007; 104(21):8851-6.

3. Peter Schroeder, Corinna Pohl, Christian Calles, Corinna Marks, Susanne Wild and Jean Krutmann; The Cellular Response to Infrared Radiation Involves Retrograde Mitochondrial Signaling Free Rad Biol Med 2007; 43:128-135.

4. Peter Voss, Hossein Hajimiragha, Martina Engels, Karsten Ruwiedel, Christian Calles, Peter Schroeder, Tilman Grune; Irradiation of GAPDH: a model for environmentally induced protein damage.) Biol Chem 2007; 388(6):583-92.

5. Verena Reimann, Ursula Krämer, Dorothee Sugiri, Kathrin Medve-Königs, Peter Schroeder, Ines Hertel, Susanne Wild, Barbara Hoffmann, Karl-Heinz Jöckel, Ulrich Ranft and Jean Krutmann; Sunbed use induces the Photoaging-Associated Mitochondrial Common Deletion in Human Skin. J Invest Dermatol 2007;128(5):1294-7

6. Peter Schroeder, Tobias Gremmel, Mark Berneburg, and Jean Krutmann; Partial Depletion of Mitochondrial DNA from Human Skin Fibroblasts Induces a Gene Expression Profile Reminiscent of Photoaged Skin; J Invest Dermatol, 2008; 128(9):2297-303.

7. Peter Schroeder, Juergen Lademann, Maxim Darvin, Helger Stege, Corinna Marks, Susanne Bruhnke, and Jean Krutmann; Analysis of the In Vivo Relevance of Infrared Radiation-Induced Signaling in Human Skin: Evidence for Skin Damage and Implications for Photoprotection. J Invest Dermatol, 2008; 128(10):2491-7

8. Peter Schroeder and Jean Krutmann; In vivo relevance of infrared a radiation-induced skin damage: Reply to Piazena and Kelleher, Letter to the Editor; Free Rad Biol Med 2008; 44(10):1870-1.

9. Elvis Pirev, Christian Calles, Peter Schroeder, Helmut Sies, Klaus-Dietrich Kroncke; Ultraviolet-A irradiation but not ultraviolet-B or infrared-A irradiation leads to a disturbed zinc homeostasis in cells. Free Rad Biol Med 2008; 45(1):86-91.

10. Nicole Buechner, Peter Schroeder, Sascha Jakob, Kerstin Kunze, Tanja Maresch, Christian Calles, Jean Krutmann, Judith Haendeler; Changes of MMP-1 and collagen type Ialpha1 by UVA, UVB and IRA are differentially regulated by Trx-1. Exp Gerontol 2008;43(7):633-7.

3. Cooperations

Es existieren zahlreiche Kooperationen sowohl inhaltlicher als auch methodischer Art mit den Projekten von LO Klotz (ROS-induzierte Signaltransduktion), F Boege (IRA vs mtDNA), J Haendeler (Entstehung des intramitochondrialen IRA Signals), und H. Sies (IRA-induzierte ROS-Bildung).