Interleukin-32.This gene encodes a member of the cytokine family.

The protein contains a

tyrosine sulfation site, 3 potential N-myristoylation sites, multiple putative phosphorylation sites,
and an RGD cell-attachment sequence. Expression of this protein is increased after the activation
of T-cells by mitogens or the activation of NK cells by IL-2. This protein induces the production
of TNF-alpha from macrophage cells. Alternate transcriptional splice variants, encoding different
isoforms, have been characterized.[1]
Interleukin 32 (IL-32) is a pro-inflammatory cytokine that can induce cells of the immune system
(such as monocytes and macrophages) to secrete inflammatory cytokines, such as tumor necrosis
factor-alpha (TNF-) and IL-6. In addition, it can also induce the production of chemokines such
as IL-8 and MIP-2 / CXCL2.[2]
IL-32 can also support osteoclast differentiation but not osteoclast activation by regulating the
MAPK/ERK pathway and the actin cytoskeleton.[3]
Interleukin 33 (IL-33) is a cytokine belonging to the IL-1 superfamily. IL-33 induces helper T
cells, mast cells, eosinophils and basophils to produce type 2 cytokines. This cytokine was
previously named NF-HEV 'nuclear factor (NF) in high endothelial venules' (HEVs) since it was
originally identified in these specialized cells.[5] IL-33 mediates its biological effects by
interacting with the receptors ST2 (also known as IL1RL1) and IL-1 Receptor Accessory Protein
(IL1RAP), activating intracellular molecules in the NF-B and MAP kinase signaling pathways
that drive production of type 2 cytokines (e.g. IL-5 and IL-13) from polarized Th2 cells. The
induction of type 2 cytokines by IL-33 in vivo is believed to induce the severe pathological
changes observed in mucosal organs following administration of IL-33.[6][7]

Structure
IL-33 is a member of the IL-1 superfamily of cytokines, a determination based in part on the
molecules -trefoil structure, a conserved structure type described in other IL-1 cytokines,
including IL-1, IL-1, IL-1Ra and IL-18. In this structure, the 12 -strands of the -trefoil are
arranged in three pseudorepeats of four -strand units, of which the first and last -strands are
antiparallel staves in a six-stranded -barrel, while the second and third -strands of each repeat
form a -hairpin sitting atop the -barrel. IL-33 is a ligand that binds to a high-affinity receptor
family member ST2. The complex of these two molecules with IL-1RAcP indicates a ternary
complex formation. The binding area appears to be a mix of polar and non-polar regions that
create a specific binding between ligand and receptor. The interface between the molecules has
been shown to be extensive. Structural data on the IL-33 molecule was determined by solution
NMR and small angle X-ray scattering.[8]

Interleukin-34, or IL-34 is a protein belonging to a group of cytokines called interleukins. It

was originally identified in humans, by large scale screening of secreted proteins; chimpanzee,
murine, rat and chicken IL-34 orthologs have also been found. The protein is composed of 241
amino acids, 39 kilodaltons in mass, and forms homodimers. IL-34 increases growth or survival

of immune cells known as monocytes; it elicits its activity by binding the Colony stimulating
factor 1 receptor.
Messenger RNA (mRNA) expression of human IL-34 is most abundant in spleen but occurs in
several other tissues: thymus, liver, small intestine, colon, prostate gland, lung, heart, brain,
kidney, testes, and ovary. The discovery of IL-34 protein in the red pulp of the spleen suggests
involvement in growth and development of myeloid cells, consistent with its activity on
monocytes.
Interleukin 35 (IL-35) is an IL-12 family cytokine produced by regulatory, but not effector, Tcells and plays a role in immune suppression. It is a dimeric protein composed of IL-12 and IL27 chains, which are encoded by two separate genes called IL12A and EBI3, respectively.
Secreted by regulatory T-cells (Tregs), IL-35 suppresses inflammatory responses of immune cells.
IL-35 is not constitutively expressed in tissues, but the gene encoding IL-35 is transcribed by
vascular endothelial cells, smooth muscle cells and monocytes after activation with
proinflammatory stimuli.
Studies in mice show the absence of either IL-35 chain from regulatory T regs reduces the cells'
ability to suppress inflammation; this has been observed during cell culture experiments and
using an experimental model for inflammatory bowel disease. To produce its suppressive effects,
IL-35 has selective activities on different T-cell subsets; it induces proliferation of Treg cell
populations but reduces activity of Th17 cell populations.