Institut für Allgemeine Pharmakologie und Toxikologie
Acute inflammation is associated with changes in cytokine, chemokine, growth factor, and mediator production that drive or modulate associated diseases and syndromes such as SIRS and Sepsis, ischemia/reperfusion injury of various tissues, or drug-induced liver injury.
In our research group we study inflammation pharmacology related to aforementioned regulatory molecules with focus on experimental acetaminophen (paracetamol, N-acetyl-p-aminophenol, APAP)-induced acute liver injury.
Overdosing of the weak-to-moderate analgesic acetaminophen is regarded as a major cause of acute liver injury worlwide and, if not timely treated with its antidote N-acetylcysteine, can proceed toward a fulminant condition requiring transplantation for patient survival. On a cellular level, liver injury by acetaminophen is regarded a two-hit process involving initial direct induction of hepatocyte cell death and, subsequent to that, activation of innate immunity that triggers an inflammatory response having the complex potential to either aggravate disease or to actually support tissue repair and hepatic regeneration:
Of note, experimental acetaminophen-induced liver injury not only is clinically significant in that specific context, but is regarded as a paradigmatic disease model relevant for a whole group of ‘cell death/sterile inflammation’-associated acute hepatic diseases. Moreover, this experimental setting is highly suitable for studying inflammation-associated liver regeneration.
Among others, we previously identified in acetaminophen-induced liver injury protective functions of recombinant IL-22 (Scheiermann P, …, Mühl H (2013) Am J Pathol 182:1107-13) and of C5aR1 signalling (Gonther S, …, Mühl H (2022) NPJ Regen Med 7:10) as well as amelioration of intoxication by pharmacologically applied IL-18BP (Bachmmann M, …, Mühl H (2018) Front Immunol 9:161).
Supported by DFG (DFG MU 1284/6-2), GRK 2336: AVE - Resolution of Inflammation, and Hessian Ministry of Higher Education, Research and the Arts (HMWK), Grant/Award Number: ACLF-I
Full publication list of Heiko Mühl:
http://loop.frontiersin.org/people/22827/overview
Prof. Dr. Heiko Mühl (group leader)
e-mail:
h.muehl@em.uni-frankfurt.de
PD Dr. Malte Bachmann (laboratory head)
e-mail:
M.Bachmann@med.uni-frankfurt.de
Ann-Chi Yu (PhD student)
e-mail:
a.yu@med.uni-frankfurt.de
Ten Selected Original Publications
Raith J, Bachmann M, Gonther S, Stülb H, Aghdassi AA, Pham CTN, and Mühl H. Targeting cathepsin C ameliorates murine acetaminophen-induced liver injury. Theranostics, 14(8): 3029, 2024
Gonther S, Bachmann M, Goren I, Huard A, Weigert A, Köhl J, and Mühl H. 3’mRNA sequencing reveals pro-regenerative properties of c5ar1 during resolution of murine acetaminophen-induced liver injury.
NPJ Regen Med., 7(1): 10, 2022
Bachmann M, Pfeilschifter J, and Mühl H. A prominent role of IL-18 in acetaminophen-induced liver injury advocates its blockage for therapy of hepatic necroinflammation.
Front Immunol., 9: 161, 2018
Scheiermann P, Bachmann M, Goren I, Zwissler B, Pfeilschifter J, and Mühl H. Application of interleukin-22 mediates protection in experimental acetaminophen-induced acute liver injury.
Am J Pathol., 182(4): 1107-1113, 2013
Kronenberger B, Rudloff I, Bachmann M, Brunner F, Kapper L, Filmann N, Waidmann O, Herrmann E, Pfeilschifter J, Zeuzem S, Piiper A, and Mühl H. Interleukin-22 predicts severity and death in advanced liver cirrhosis: A prospective cohort study.
BMC Medicine, 10 (1), 102, 2012
Bachmann M, Scheiermann P, Härdle L, Pfeilschifter J, and Mühl H. IL36γ/IL1F9 - an innate T-bet target in myeloid cells.
J Biol Chem., 287(50): 41684-41696, 2012
Bachmann M, Horn K, Rudloff I, Goren I, Holdener M, Christen U, Darsow N, Hunfeld KP, Koehl U, Kind P, Pfeilschifter J, Kraiczy P, and Mühl H. Early production of IL-22 but not IL-17 by peripheral blood mononuclear cells exposed to live Borrelia burgdorferi: the role of monocytes and IL-1.
PLoS Pathogens, 14;6(10): e1001144, 2010
Sadik CD, Bachmann M, Pfeilschifter J, and Mühl H. Activation of interferon regulatory factor-3 via Toll-like receptor 3 and immunomodulatory functions detected in A549 lung epithelial cells exposed to misplaced U1-snRNA.
Nucleic Acids Res, 37(15): 5041-5056, 2009
Ziesché E, Bachmann M, Kleinert H, Pfeilschifter J, Mühl H. The IL-22/STAT3 pathway potentiates expression of iNOS in human colon carcinoma cells.
J Biol Chem., 282(22), 16006-16015, 2007
Paulukat J, Bosmann M, Nold M, Garkisch S, Kämpfer H, Frank S, Raedle J, Zeuzem S, Pfeilschifter J, Mühl H. Expression and release of IL-18 binding protein in response to Interferon-g.
J Immunol., 167(12): 7038-7043, 2001
Selected Reviews
Mühl H, Bachmann M. IL-18/IL-18BP and IL-22/IL-22BP: Two interrelated couples with therapeutic potential.
Cell Signal., 63: 109388, 2019
Mühl, H. STAT3, a key parameter of cytokine-driven tissue protection during sterile inflammation – the case of experimental acetaminophen (paracetamol)-induced liver damage.
Front Immunol. 7: 163, 2016
Mühl H, Scheiermann P, Bachmann M, Härdle L, Heinrichs A, and Pfeilschifter J. IL-22 in tissue protective therapy.
Br J Pharmacol., 169(4): 761-771. 2013
Mühl, H. Pro-Inflammatory Signaling by IL-10 and IL-22: Bad Habit Stirred up by Interferons?
Front. Immunol., 4: 18, 2013
Mühl H, Bachmann M and Pfeilschifter J. Inducible NO synthase and antibacterial host defense in times of Th17/Th22/T22 immunity.
Cell Microbiol., 13(3): 340-348, 2011
Mühl H, Pfeilschifter J. Interleukin-18 bioactivity: a novel target for immunopharmacological anti-inflammatory intervention.
Eur J Pharmacol., 500(1-3): 63-71, 2004
Mühl H, Pfeilschifter J. Anti-inflammatory properties of pro-inflammatory interferon-gamma.
Int Immunopharmacol., 3(9): 1247-1255, 2003