TNF
(TUMOR NECROSIS FACTOR) a multifunctional
cytokine, with effects on lipid metabolism, coagulation, insulin resistance,
and endothelial function.
Metabolism and immunity are closely linked.
Both overnutrition and undernutrition have implications for
immune function. Starvation and malnutrition can suppress
immune function and increase susceptibility to infections.
Obesity is associated with a state of aberrant immune activity
and increasing risk for associated inflammatory diseases,
including atherosclerosis, diabetes, airway inflammation,
and fatty liver disease. Thus, optimal nutritional and metabolic
homeostasis is an important part of appropriate immune function
and good health.
Kathryn E. Wellen and Gökhan S. Hotamisligil.
J. Clin. Invest. 115:1111-1119 (2005)
Lipids and inflammatory mediators: integration
of metabolic and immune responses in adipocytes and macrophages
through shared mechanisms. Under normal conditions, adipocytes
store lipids and regulate metabolic homeostasis, and macrophages
function in the inflammatory response, although each cell
type has the capacity to perform both functions. In obesity,
adipose tissue becomes inflamed, both via infiltration of
adipose tissue by macrophages and as a result of adipocytes
themselves becoming producers of inflammatory cytokines. Inflammation
of adipose tissue is a crucial step in the development of
peripheral insulin resistance. In addition, in proatherosclerotic
conditions such as obesity and dyslipidemia, macrophages accumulate
lipid to become foam cells. Adipocytes and macrophages share
common features such as expression of cytokines, FABPs, nuclear
hormone receptors, and many other factors. As evidenced by
genetic loss-of-function models, adipocyte/macrophage FABPs
modulate both lipid accumulation in adipocytes and cholesterol
accumulation in macrophages, as well as the development of
insulin resistance and atherosclerosis. PPAR and LXR pathways
oppose inflammation and promote cholesterol efflux from macrophages
and lipid storage in adipocytes.
Kathryn E. Wellen and Gökhan S. Hotamisligil.
J. Clin. Invest. 115:1111-1119 (2005)
Model of overlapping metabolic and inflammatory
signaling and sensing pathways in adipocytes or macrophages.
Inflammatory pathways can be initiated by extracellular mediators
such as cytokines and lipids or by intracellular stresses
such as ER stress or excess ROS production by mitochondria.
Signals from all of these mediators converge on inflammatory
signaling pathways, including the kinases JNK and IKK. These
pathways lead to the production of additional inflammatory
mediators through transcriptional regulation as well as to
the direct inhibition of insulin signaling. Other pathways
such as those mediated through the SOCS proteins and iNOS
are also involved in inflammation-mediated inhibition of insulin
action. Opposing the inflammatory pathways are transcription
factors from the PPAR and LXR families, which promote nutrient
transport and metabolism and antagonize inflammatory activity.
More proximal regulation is provided by FABPs, which likely
sequester ligands of these transcription factors, thus promoting
a more inflammatory environment. The absence of FABPs is antiinflammatory.
The cell must strike a balance between metabolism and inflammation.
In conditions of overnutrition, this becomes a particular
challenge, as the very processes required for response to
nutrients and nutrient utilization, such as mitochondrial
oxidative metabolism and increasing protein synthesis in the
ER, can induce the inflammatory response. IR, insulin receptor.
Wellen and Gökhan S. Hotamisligil. J.
Clin. Invest. 115:1111-1119 (2005)
Nutrient and pathogen sensing or response systems have important
overlapping features, and their modulation by obesity or infection
can lead to overlapping physiological outcomes. For example,
the chronic inflammation of obesity leads to elevated plasma
lipid levels and the development of insulin resistance, eventually
resulting in fatty liver disease, atherosclerosis, and diabetes.
Infection typically leads to a more transient and robust inflammatory
response and short-term hyperlipidemia that aids in the resolution
of the infection. In some circumstances of chronic infection,
however, insulin resistance, diabetes, and atherosclerosis
can result.
Wellen and Gökhan S. Hotamisligil. J.
Clin. Invest. 115:1111-1119 (2005)
A simplified diagram of the innate immune response to infection
and tissue injury involving the inflammatory cytokines and
the coagulation cascade. –ve = negative; +ve = positive;
PAI1 = platelet-activation inhibitor-1; ICAM = intracellular
adhesion molecule.
Cheryl L, et al. Chest. 2003;124:1103-1115
Structure of the TNF genes. The locations of MHC loci are
shown. Hatched boxes indicate the relative positions of the
indicated loci. Open boxes represent the untranslated portions
of the TNF exons, and closed boxes represent translated portions.
Lines indicate introns (areas of the gene that are spliced
out of the mature RNA product). Arrows indicate the transcriptional
orientation of the genes. Reprinted with permission by Webb
et al.26 kb = kilobase. C2 = complement component 2; Bf =
complement factor B; C4A = complement component 4A; C4B =
complement component C4B; 21-OH = 21-hydroxylase.
Cheryl L, et al. Chest. 2003;124:1103-1115
Map of the human TNF locus and HLA loci based upon the studies
of Wilson et al. (61) and Zanelli et al. (64). The drawing
indicates the relative positions of the TNFA and TNFB genes
encoding TNF- and TNF-ß, respectively, with respect to HLA
regions on human chromosome 6p. Rectangles indicate genes,
and horizontal arrows above genes show the direction of transcription.
Vertical arrows indicate the positions of markers used in
this study. These include the polymorphic TNF MSM repeat upstream
of TNFB; the RFLP marker for TNF1 and TNF2 alleles in the
TNFA promoter, located at position -307 (called -308 in the
literature) with respect to transcription; and three MSMs
in flanking HLA regions. HSP70-2/1 indicates the location
of the HSP70-2 (centromeric) and HSP70-1 (telomeric) genes.
Distances between regions, marked with double-headed arrows,
are indicated in kilobases or megabases. The figure is not
drawn to scale.
Karplus T.M., et al. Infection and Immunity,
December 2002, p. 6919-6925, Vol. 70, No. 12
Effect of salicylates on insulin signaling
during insulin resistance. (a) Normally, the occupied insulin
receptor phosphorylates scaffold proteins, such as the IRS-1,
on critical tyrosine residues. However, in insulin-resistant
states, a number of agents, such as the cytokine TNF- or circulating
FFAs, lead through intermediary signaling pathways to the
activation of IKK, which in turn indirectly increases the
number of phosphorylated serine and threonine residues (indicated
by blue circles) on IRS-1. This modification blocks the tyrosine
phosphorylation and converts IRS-1 into an insulin receptor
inhibitory protein. (b) In the presence of salicylates, IKK
activity is inhibited, reducing the IRS-1 serine/threonine
phosphorylation and allowing IRS-1 to be phosphorylated on
tyrosine. These phosphorylated tyrosine residues (black squares)
serve as binding sites for a number of signaling molecules,
most importantly PI 3'-kinase, which initiate signaling pathways
regulating metabolism. Aspirin (ASA) also inhibits cyclooxygensases
(COX) to prevent the generation of inflammatory prostaglandins
(PGE) from arachidonic acid (AA) in a pathway unrelated to
the effects of the drug on insulin action.
Morris J. Birnbaum. J Clin Invest, September
2001, Volume 108, Number 5, 655-659
Proposed pathophysiology of hypertension through inflammatory
mechanisms (see Section II). CNS, Central nervous system; SNS,
sympathetic nervous system. José Manuel Fernández-Real and Wifredo
Ricart . Endocrine Reviews 24 (3): 278-301
Balance of proinflammatory and antiinflammatory
agents regulating the acute-phase response. An adequate balance
will lead to resolution of the process.
José Manuel Fernández-Real and Wifredo
Ricart . Endocrine Reviews 24 (3): 278-301
TNF
a multifunctional cytokine,
with effects on lipid metabolism, coagulation,
insulin resistance, and endothelial function.
TNF-alpha and TNF-beta
similar biologic activities,
share 30% amino acid homology and a common
receptor
TNF-alpha
a trimeric
glycoprotein active in both membrane bound
and secreted forms
