Up regulation of IL-6 by ischemic preconditioning in normal and fatty rat livers: association with reduction of oxidative stress
Authors: Cristina De Ponti
Marta Massip
Gaetano Cairo
Carmen Peralta
Joan Rosellò-Catafau
Lorenza Tacchini
Journal: Free Radical Research (2006)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: IL-6; ischemic preconditioning; hepatic ischemia reperfusion; oxidative damage; fatty livers
Affiliations: Institute of General Pathology, University of Milano, via Mangiagalli 31, 20133, Milano, Italy.

Abstract:  We analyzed the role of IL-6 in the protection that ischemic preconditioning (IP) exerts against hepatic ischemia reperfusion-mediated (I/R) oxidative damage, particularly in fatty livers. IP-related IL-6 up-regulation during reperfusion in steatotic and non-steatotic livers was correlated with reduced indices of liver damage, as also demonstrated by pharmacological modulation of IL-6. IP activated NF-kB and HSF during ischemia (Isc), whereas AP-1 activity was unaffected. IP blunted the activation of STAT3 and stress-responsive genes, such as NF-kB, AP-1 and heme oxygenase (HO-1) during reperfusion. The role of reduced oxidative stress in hepatoprotection of fatty livers was further demonstrated by the fact that: (i) IP prevented the decrease of glutathione levels and the increase of lipid peroxidation; (ii) the anti-oxidant GSH-ester prevented lipid peroxidation and necrosis. In conclusion, IP modulates the activity of transcription factors and triggers IL-6 production; this may prevent hepatic I/R damage in a oxidative stress-dependent way, particularly in fatty livers. 

Retracted: Yes

PubPeer comments:
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 #1 See also Fig 3D from [Gammella, Cairo Tacchini (2010)] . ![] , 
 Fig 5A.  EMSA analysis of NF-kB, AP-1 and Oct-1 activities in livers of Ln and Ob rats. THe Ln and Ob halves of the Oct-1 band are indistinguishable and cancel out remarkably well when one is black-white reversed and superimposed on the other. ![file] , 
 #3 Thank you for this remark. Fifteen years after publication, the original data for these figures were not available for evaluation. However, the findings of this paper are confirmed by the results of complementary experiments presented in the article, and the principal conclusion was further confirmed by other labs (please see for example Wruck CJ 2011 J Biol Chem), so that the paper has been cited in several highly quoted reviews covering the field and written by independent authors (please see for example Abu-Amara M 2010 Liver Transplantation) , 
 #3 Appreciate your diligence at documenting this concern. Based on your work, to me there appear to be reused and manipulated images in these papers; in my opinion, this is not a close call. I do understand the authorsu2019 challenges in finding original data at this point, however the authorsu2019 other points do not address the concerns about the images. , 
 #5 It is actually hard for us to agree or disagree by inspection that the images were reused. The paper is almost 15 years old and therefore, unfortunately, itu2019s impossible for us to retrieve and evaluate the original images (e.g. the ethidium bromide-stained rRNA bands) used for this figure. However, we would like to remark that the bandshift indicated by the reviewer regards a loading control using the transcription factor Oct-1, which is evenly and uniformly expressed. Therefore, it is expected that all the bands look alike. In addition, the bands are not neat; no wonder that the superimposition shows a similar pattern. Anyway, in Fig 5A, we showed differences in the DNA binding activities of NF-kB and AP-1 so impressive (up to 27-fold) that inaccurate sample loading could not have altered the result. Please also note that the induction of these transcription factors by stress conditions was already well known at the time of the study and Fig 5A shows a sort of confirmatory experiment (in addition to the effect of preconditioning). In case of inadvertent error in the figure preparation, which cannot be presently confirmed or disproved, we sincerely apologize, but we would like to remark that the hypothetical use of the same image, though inappropriate, does not affect the results and conclusions of this work, which have been independently confirmed (e.g. Wruck CJ 2011 J Biol Chem), so that the paper has been cited in several highly quoted reviews covering the field (please see for example Abu-Amara M 2010 Liver Transplantation) , 
 #6 As I said previously, I appreciate the difficulty in retrieving records that are 15 years old. Would you have records for the 9 year old paper that appears to use the same image? An uncropped original would go a long ways toward addressing these concerns. Journal of Neuroscience Research (2010) pubmed: 20143408 doi: 10.1002 jnr.22366 issn: 0360-4012 issn: 1097-4547 , 
 Retracted [20 July 2022] . ------------------------ We, the Authors, Editor and Publisher of Free Radical Research, have retracted the following article: Lorenza Tacchini, Gaetano Cairo, Cristina De Ponti, Marta Massip, Joan Rosellu00f2-Catafau Carmen Peralta: u2018Up regulation of IL-6 by ischemic preconditioning in normal and fatty rat livers: Association with reduction of oxidative stressu2019 40:11 1206-1217 (2006) DOI 10.1080 10715760600885432. Since the above article was published, the Publisher and Editor in Chief of Free Radical Research have been made aware of concerns regarding image manipulation in figures 5A and 5B, and similarities between these figures and the following figures published in the other articles by the authors: - Figures 6A and 7A Cristina De Ponti, Rita Carini, Elisa Alchera, Maria Paola Nitti, Massimo Locati, Emanuele Albano, Gaetano Cairo, Lorenza Tacchini u2018Adenosine A2a receptoru2010mediated, normoxic induction of HIFu20101 through PKC and PIu20103Ku2010dependent pathways in macrophagesu2019 Journal of Leukocyte Biology, 82(2): 392-402 (2007) DOI 10.1189 jlb.0107060. - Figure 3D Elena Gammella, Gaetano Cairo, Lorenza Tacchini, u2018Adenosine A(2)A receptor but not HIF-1 mediates Tyrosine hydroxylase induction in hypoxic PC12 cellsu2019 Journal of Neuroscience Research 88(9): 2007-16 (2010) DOI 10.1002 jnr.22366. The authors have been unable to provide the original image data on request due to the data no longer being available (after 15 years) and are unable to explain the duplications in figures 5A and 5B. As a result, the findings shown in these figures are no longer reliable. We have been informed in our decision-making by our policy on publishing ethics and integrity and the COPE guidelines on retractions. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as u2018Retractedu2019 ,