Hepatic ischemia/reperfusion (I/R) results in a neutrophildependent lung and liver injury. The process of neutrophil recruitment and activation in this injury is at least partially dependent on the presence of the ELR؉ CXC chemokines. Other investigations have shown that ELR؊ CXC chemokines can block ELR؉ CXC chemokine neutrophil recruitment and activation in vitro. To begin to investigate the role of the balance between these 2 types of molecules in vivo in neutrophil recruitment and activation following hepatic I/R, we used our rat model of lobar hepatic I/R and pretreated animals with pharmacologic doses of gamma-interferon (␥-IFN). ␥-IFN is known to upregulate some of the ELR؊ CXC chemokines, including ␥-IFN-inducible protein (IP-10) and monokine-induced by ␥-IFN (MIG), as well as down-regulate ELR؉ CXC chemokine production. Following hepatic I/R or sham laparotomy, hepatic and pulmonary levels of the ELR؊ chemokines, IP-10 and MIG, and the ELR؉ chemokines, rat cytokine-induced neutrophil chemoattractant (KC), macrophage inflammatory protein-2 (MIP-2), and epithelial neutrophil activating protein (ENA-78) were determined by ELISA, and lung and liver injury were assessed. In response to ␥-IFN, hepatic and pulmonary levels of the ELR؊ chemokines were increased and the levels of the ELR؉ chemokines were decreased. Immunohistochemical staining confirmed the hepatocyte as the source of these molecules, as well as the changes in chemokine levels in response to ␥-IFN. There was an associated significant decrease in liver and lung injury, although there was no significant decrease in neutrophil influx in either tissue. This suggests that the alteration in the balance of ELR؉ to ELR؊ CXC chemokines results in a decrease in tissue injury through a mechanism other than through an alteration in tissue neutrophil levels. (HEPATOLOGY 2000;31: 435-445.)
Cytokine-mediated communication between the various cell types found at sites of inflammation is critical for the successful orchestration of the inflammatory response and the subsequent resolution of tissue injury. The proinflammatory cytokines tumor necrosis factor-␣ (TNF) and gammainterferon (␥-IFN) have been shown to exert pleiotropic effects in a variety of pathophysiologic states including sepsis, ischemia/reperfusion injury, viral infections, fungal infections, and other inflammatory states such as pancreatitis. Depending on the setting, these cytokines may function cooperatively or antagonistically to regulate expression of a variety of other cytokines, chemokines, and adhesion molecules. In general, ␥-IFN is considered to be an enhancer of cellular immune function. [1][2][3] It is known to modulate antigen presentation, cellular differentiation, cytotoxicity, cytokine production, cellular adhesion, and oxidative metabolism through its effects on leukocytes and endothelial cells. 1-3 ␥-IFN is an important macrophage activating factor. 4 As such, it regulates numerous macrophage functions including tumor cell cytotoxicity, antimicrobial activity, increased killing of intracellular pathogens, and antigen processing and presentation to lymphocytes through the induction of MHC antigens. 3 Investigations have shown that ␥-IFN modulates Kupffer cell production of TNF and interleukin-1 (IL-1), although via different mechanisms. 5 ␥-IFN increases Kupffer cell production of TNF and prostaglandin E2 (PGE2), but not IL-1; further, PGE2 is a known inhibitor of Kupffer cell TNF release via a negative feedback loop, thus suggesting an autoregulatory feedback mechanism involving ␥-IFN. 5a The CXC chemokines are a group of molecules that have both inflammatory and reparative properties and are best known for their neutrophil chemotactic properties. 6,7 Many members of this family have been described and include ENA-78, MIP-2, IL-8, IP-10, MIG, and platelet factor-4 (PF-4). 6,7 IL-8 is the most well-studied CXC chemokine and is produced by many cell types in response to TNF and IL-1, including monocytes, alveolar macrophages, neutrophils, keratinocytes, mesangial cells, epithelial cells, hepatocytes, Abbreviations: I/R, ischemia/reperfusion; ␥-IFN, gamma-interferon; CXC chemokines, a family of chemotactic cytokines that are basic heparin-binding proteins that have 4 conserved cysteine amino acids, with the first 2 cysteines separated by 1 nonconserved amino acid, hence the designation CXC; ELR motif, the 3 amino acid residues that immediately precede the first cysteine amino acid in the CXC chemokine family. These are critically important in receptor binding and neutrophil activation.