Ch.

4 The Role of Cytokines as Mediators of the Inflammatory Response Inflammation pathologic rxn whereby fluid & circulating leukocytes accumulate in extravascular tissues in response to injury or infection protective response to permit higher forms of life to rid themselves of injurious agents, remove necrotic cells, cellular debris, & repair damage to tissues/organs Septic Shock clinical manifestation of a systemic inflammatory response run amok Severe sepsis occurs in ~ 750k people in U.S., 30% mortality rate Basic Definitions & Classification Systems Cytokines o small CHONs or glycoproteins secreted for purpose of altering fct of target cells in an endocrine, paracrine, or autocrine fashion o pleiotropic- capable of inducing many different biologic effects Type I Cytokines o IL-2, 3, 4, 5, 6, 7, 9, 11, 13, 15; G-CSF Type II Cytokines o IFN-, , ; IL-10 TH1-proinflammatory o Direct cell-mediated immune responses nec for eradication of intracellular pathogens o Favor macrophage activation o Produce IL-2, IFN-, lymphotoxin-

TH2- anti-inflammatory o Pathogenesis of atopy & allergic inflammation o Favor B-cell growth & differentation o Produce IL-4, 5, 6, 9, 10, 13 Chemokines- ability to act as chemoattractants for leukocytes or fibroblasts o CSFs- act to stimulate growth &/or differentation of hematopoietic progenitor cells IFN- o Produced by 3 cell types: CD4 TH1 cells CD8 TH1 cells NK cells o Act with IL-12 & IL-18 to promote differentation of CD4 T cells to TH1 phenotype o Acts as positive feedback loop for CD4 T cells o IL-12 & IL-18, produced by monocytes & macrophages stimulate production of IFN- o Inhibits differentation of lymphocytes into TH2 cells o Downregulates production of IL-4 & IL-10 o Induces expression of proteins involved in innate immune response to microbes o Signal transduction via CHON tyrosine phosphorylation cascade, aka JAK-STAT pathway IL-1 & TNF o Pluripotent cytokines, activate helper T cells, IL-1, & TNF o Promote nearly all types of humoral & cellular immune

responses o Activate neutrophils & macrophages IL-1 o Synthesized by monocytes, macrophages, B lymphocytes, T lymphocytes, NK cells, Keratinocytes, dendritic cells, fibroblasts, neutrophils, endothelial cells, enterocytes TNF o