title: Upregulation of Programmed Death-1 and Its Ligand in Cardiac Injury Models: Interaction with GADD153.
abstract: OBJECTIVE
  Programmed Death-1 (PD-1) and its ligand, PD-L1, are regulators of immune/ inflammatory mechanisms. We explored the potential involvement of PD-1/PD-L1 pathway in the inflammatory response and tissue damage in cardiac injury models.
  
  
  METHODS
  Ischemic-reperfused and cryoinjured hearts were processed for flow cytometry and immunohistochemical studies for determination of cardiac PD-1 and PD-L1 in the context of assessment of the growth arrest- and DNA damage-inducible protein 153 (GADD153) which regulates both inflammation and cell death. Further, we explored the potential ability of injured cardiac cells to influence proliferation of T lymphocytes.
  
  
  RESULTS
  The isolated ischemic-reperfused hearts displayed marked increases in expression of PD-1 and PD-L1 in cardiomyocytes; however, immunofluorescent studies indicate that PD-1 and PD-L1 are not primarily co-expressed on the same cardiomyocytes. Upregulation of PD-1/PD-L1 was associated with a) marked increases in GADD153 and interleukin (IL)-17 but a mild increase in IL-10 and b) disruption of mitochondrial membrane potential (ψm) as well as apoptotic and necrotic cell death. Importantly, while isotype matching treatment did not affect the aforementioned changes, treatment with the PD-L1 blocking antibody reversed those effects in association with marked cardioprotection. Further, ischemic-reperfused cardiac cells reduced proliferation of T lymphocytes, an effect partially reversed by PD-L1 antibody. Subsequent studies using the cryoinjury model of myocardial infarction revealed significant increases in PD-1, PD-L1, GADD153 and IL-17 positive cells in association with significant apoptosis/necrosis.
  
  
  CONCLUSIONS
  The data suggest that upregulation of PD-1/PD-L1 pathway in cardiac injury models mediates tissue damage likely through a paracrine mechanism. Importantly, inhibition of T cell proliferation by ischemic-reperfused cardiac cells is consistent with the negative immunoregulatory role of PD-1/PD-L1 pathway, likely reflecting an endogenous cardiac mechanism to curtail the deleterious impact of infiltrating immune cells to the damaged myocardium. The balance of these countervailing effects determines the extent of cardiac injury.
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, Georgia 30912, United States of America.
authors.forename: Babak
authors.initials: B
authors.lastname: Baban
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, Georgia 30912, United States of America.
authors.forename: Jun Yao
authors.initials: JY
authors.lastname: Liu
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, Georgia 30912, United States of America.
authors.forename: Xu
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Medicine, Section of Cardiology and the Vascular Biology Center, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, United States of America.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
authors.affiliation: Department of Oral Biology, College of Dental Medicine, Georgia Regents University, Augusta, Georgia 30912, United States of America.
authors.forename: Mahmood S
authors.initials: MS
authors.lastname: Mozaffari
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D002316:Cardiotonic Agents / Q000494:pharmacology; D002450:Cell Communication; D049109:Cell Proliferation; D018920:Coculture Techniques; D005615:Freezing; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D061251:Primary Cell Culture; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D051742:Transcription Factor CHOP / Q000235:genetics* / Q000378:metabolism
chemical_list: D057134:Antibodies, Neutralizing; D060890:B7-H1 Antigen; D002316:Cardiotonic Agents; C498919:Cd274 protein, mouse; C497250:Ddit3 protein, mouse; D020381:Interleukin-17; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D051742:Transcription Factor CHOP