Bacterial
lipopolysaccharide (LPS) is recognized by several receptors, including the
toll-like receptor (TLR) 4, on various cells. Among many biological responses to LPS is
fever, an often polyphasic rise in body temperature that is thought to be mediated by
prostaglandin (PG) E(2). Which receptors on which cells are linked to
fever production is unknown. It is also unknown which cells produce
PGE(2) that triggers the earliest (first) phase of
fever. Two recent studies from our group answer these questions. In the first one, we studied LPS-induced
fever in mouse chimeras selectively lacking the TLR4 in hematopoietic or nonhematopoietic cells. We found that the first phase of
fever is triggered via the TLR4 on hematopoietic cells. In the second study, we investigated LPS
fever in rats. We found that the number of cells expressing
cyclooxygenase (COX)-2, a PGE(2)-synthesizing
enzyme, surged at the onset of
fever in the lung and liver (but not in the brain), and that most of these cells were macrophages. Because LPS-induced
PGE(2) production in macrophages is TLR4-dependent, it is tempting to speculate that the TLR4-bearing, bone marrow-derived cells implicated in
fever pathogenesis by the first study are the same as the COX-2-positive macrophages identified in the second study. Hence, pulmonary and hepatic macrophages that recognize LPS via the TLR4 and rapidly produce
PGE(2) are likely triggers of the
fever response.