by the presence of cytokines: ifnγ increases the rate of apoptosis, whereas il-10 and tgf-β decrease it. however, il-10 has counterproductive effects on the immune system, and has been shown to actually promote infection by foreign pathogens. the role of il-10 in bacterial and parasitic infection has been discovered as a strategy to evade host immune systems. there are bacteria which parasitize ams by invading through their membranes, and thrive by growing and replicating inside of them, exploiting ams as host cells. normally, this infection can be eliminated by t-cells, which activate enzymes in alveolar macrophages that destroy the bacteria; but these bacteria have been shown to alter the cytokine signaling network to their advantage. as an inhibitory cytokine, il-10 facilitates the infection of human alveolar macrophages and monocytes by completely reversing the protective effect of ifnγ against intracellular legionella pneumophila replication. yersinia enterocolitica has also been shown to releases virulence antigen lcrv, which induces il-10 through toll-like receptor-2 and cd14 (an accessory surface protein of tlr4-mediated lps-signaling), resulting in the suppression of ifnγ and tnf-alpha suppression. transforming growth factor β (tgf-β) in normal conditions, alveolar macrophages adhere closely to alveolar epithelial cells, thus inducing the expression of the αvβ6 integrin. integrins are dimeric cell-surface receptors composed of alpha and beta subunits, which activates tgf-β.< tgf-β is a multifunctional cytokine that modulates a variety of biological processes such as cell growth, apoptosis, extracellular matrix synthesis, inflammation, and immune responses. tgf-β tightly regulates anti-inflammatory activity by suppressing pro-inflammatory cytokine production, thereby inhibiting t-lymphocyte function. integrins avβ6 and avβ8 sequester latent tgf-β to the cell surface, where activation can be tightly coupled to cellular responses to environmental stress in the maintenance of homeostasis; integrins also localize activated tgfβ in the vicinity of the macrophages. normally mature tgfβ is secreted as a latent complex with its n-terminal fragment, latency-associated peptide (lap), which inhibits its activity. the latent complex is covalently linked to the extracellular matrix by binding to latent tgf-β-binding proteins. tgf-β is activated by diverse mechanisms in the lung, ultimately involving either proteolysis or conformational alteration of the lap. αvβ6 integrin is able to mediate activation of tgf-β by binding to tgf-β1 lap, which serves as a ligand binding site for the integrin, and is an essential component of the tgf-β activation apparatus. once activated, tgfβ leads to the suppression of macrophage functionality (cytokine production and phagocytosis). binding of activated tgf-β to its receptors expressed on alveolar macrophages induces a downstream signaling cascade, including phosphorylation of receptor-regulated small mothers against decapentaplegic (r-smad)homologs 2 and 3. phosphorylated smad-2 and -3 then form heteromeric complexes with common-mediator smad 4 (co-smad-4). once assembled, the complexes translocates into the nucleus via the nuclear pore with the assistance of importins alpha/beta. once in the nucleus, these complexes accumulate and eventually act as a transcription factors, regulating the expression of tgf-β target genes. thus tgf-β signaling involves a direct pathway from the receptors on the surface of a cell to the nucleus. activation toll-like receptors (tlrs) are signaling prrs, capable of recognizing various bacterial proteins. although bacteria have evolved means of evading host defense mechanisms, they express pamps, such as lipoglycans and lipoproteins that are recognized by cells of the innate immune system through the tlrs. upon binding of pamps to tlrs, the tlr triggers inflammatory and defensive responses in the host cell, inducing actin polymerization in alveolar macrophages (a crucial component in endocytosis and motility). actin polymerization in alveolar macrophages causes the suppression of integrin expression, which in turn causes the deactivation of tgf-β and the downregulation of the basal phosphorylation level of smad 2/3; subsequently leading to the activation and detachment of alveolar macrophages from the alveolar epithelial cells . upon activation, macrophages become primed for phagocytosis and begin to secrete proinflammatory cytokines (tnf-α and il-6). the priming of macrophages involves the enhancement of respiratory burst activity by ifn-γ and tnf-α. ifnγ induces both an increased affinity of the nadph oxidase for nadph in macrophages, as well as an increased rate of gene transcription and message expression for gp91phox protein. tnf-α acts as an autocrine stimulus by increasing the expression of both p47phox and p67phox transcripts. the rois produced during the respiration burst response, in turn, enhance production of tnf-α by macrophages. deactivation gas exchange must be restored as quickly as possible to avoid collateral damage, so activated lymphocytes secrete ifnγ to stimulate the production of matrix metalloproteinase mmp-9 by macrophages. ams have been reported to produce mmp-9 partly via pge2-dependent pka signaling pathways, which are the pathways involved in the inhibition of phagocytosis. mmp-9 activates latent tgf-β, reinducing expression of αvβ6 integrins on alveolar epithelial cells, thereby returning the alveolar macrophage to a resting state. activation of tgf-β is also advantageous because its production stimulates collagen synthesis in interstitial fibroblasts, which is necessary for restoring alveolar wall architecture.