Inhibition of p38 pathway suppresses human islet production of pro-inflammatory cytokines and improves islet graft function

Am J Transplant. 2005 Mar;5(3):484-93. doi: 10.1046/j.1600-6143.2004.00716.x.


Nonspecific inflammation is associated with primary graft nonfunction (PNF). Inflammatory islet damage is mediated at least partially by pro-inflammatory cytokines, such as interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) produced by resident islet macrophages. The p38 pathway is known to be involved in cytokine production in the cells of the monocyte-macrophage lineage. Therefore, inhibition of the p38 pathway may prevent pro-inflammatory cytokine production by resident islet macrophages and possibly reduce the incidence of PNF. Our present study has demonstrated that inhibition of the p38 pathway by a chemical p38 inhibitor, SB203580, suppresses IL-1beta and TNF-alpha production in human islets exposed to lipopolysaccharide (LPS) and/or inflammatory cytokines. Although IL-1beta is predominantly produced by resident macrophages, ductal cells and islet vascular endothelial cells were found to be another cellular source of IL-1beta in isolated human islets. SB203580 also inhibited the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in the treated islets. Furthermore, human islets treated with SB203580 for 1 h prior to transplantation showed significantly improved graft function. These results suggest that inhibition of the p38 pathway may become a new therapeutic strategy to improve graft survival in clinical islet transplantation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology
  • Cell Death / drug effects
  • Cyclooxygenase 2
  • Cytokines / metabolism*
  • Humans
  • Imidazoles / pharmacology
  • Inflammation / metabolism*
  • Interferon-gamma / metabolism
  • Interleukin-1 / metabolism
  • Islets of Langerhans / drug effects*
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / metabolism
  • Islets of Langerhans Transplantation
  • Lipopolysaccharides / metabolism
  • Membrane Proteins
  • Mice
  • Nitric Oxide Synthase / biosynthesis
  • Nitric Oxide Synthase / genetics
  • Nitric Oxide Synthase Type II
  • Prostaglandin-Endoperoxide Synthases / biosynthesis
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Pyridines / pharmacology
  • Tumor Necrosis Factor-alpha / biosynthesis
  • Tumor Necrosis Factor-alpha / genetics
  • p38 Mitogen-Activated Protein Kinases / antagonists & inhibitors*


  • Anti-Inflammatory Agents, Non-Steroidal
  • Cytokines
  • Imidazoles
  • Interleukin-1
  • Lipopolysaccharides
  • Membrane Proteins
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Interferon-gamma
  • NOS2 protein, human
  • Nitric Oxide Synthase
  • Nitric Oxide Synthase Type II
  • Nos2 protein, mouse
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • p38 Mitogen-Activated Protein Kinases
  • SB 203580