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1990). The cytoplasmic domain contains Ser/Pro-ricb regions similar to

those found in the 1L-2RP and GM-CSFR p chains and the extraceUuUar

domain contains a WSXWS motif characteristic of cytokine receptors. The

lL-4Ra chain is distributed in low numbers on pre B cells, resting B cells

and resting T cells and in high numbers after activation (Law et al., 1991;

Starkey, 1991; Zola et al., 1993; Degiannis et al., 1993). It is also present

endothelial cells, epithelial cells, fibroblasts, muscle cells, neuroblasts, brain stroma and marrow stroma (Varriccbio et al., 1993; Banchereau et al., 1994b).

The second chain of the lL-4 receptor is the yc chain. The presence of the yc augments IL-4 binding and enhances proliferative responses to IL-4 in mouse cell bnes (Russell et al., 1993; Noguchi et al., 1993a). i^^I-labelled IL-4 cross-linking of the receptor chains showed that p 140 and yc are

associated in the high affinity 1L-4R complex. Immunoprecipation of the cross-linke^ complex with anti p 140 antibody or anti yc antisera also yielded bands corresponding to p l40 and yc.

Substitution analysis of evolutionari/jconserved regions and of the

carboxyl terminus identified 3 amino acids important for lL-4 binding and activation (Kruse et al., 1991; Kruse et al., 1992; Reusch et al., 1994; Kruse et al., 1993; Tony et al., 1994; Duschl et al., 1995). Residues E9 (glutamic acid) and R88 (arginine)‘>1 when substituted with glutamine (Q) or aspartic acid (D^ respectively^severely impair lL-4 binding hut not activation. This supported the structural model where residues E9 and R88 are in close proximity.

In contrast, mutations at residue 124 from tyrosine to aspartic acid

(Y124D) severely affected the biological activity of the protein without any significant effect on receptor binding (Kruse et al., 1992; Kruse et al..

62

1993; Tony et al., 1994; Duschl et al., 1995). This mutation appears to be

directly analogous to the IL-2 Q141D protein (Zurawski et al., 1990)

indicating that Y124 may interact with another subunit of the receptor

required for activation, possibly the yc chain.

1,4,4 I n te r le u k in - 13

IL-13 shares structural sim ilarities with members of the haematopoietin

cytokine superfamily. Circular diochroism (CD) analysis of mIL-13 shows

it to have the characteristics consistent with highly a-helical proteins such

as haematopoietins (Zurawski and de Vries, 1994). The 3D structure of IL-

13 has not been determined. Computer modelling based on conserved structural regions from members of the haematopoietic cytokine family

have produced two structural models for IL-13 (Bamborough et al., 1994).

The models indicate that IL-13 is more similar to GM-CSF than other

cytokines in terms of lengths of its helices and more similar to IL-4 in

terms of lengths of loops.

Cellular sources of IL-13

Human IL-13 is produced by both CD4+ and CD8+ activated T cells and

can be induced by either antigen-specific or polyclonal stim uli (Minty et

al., 1993; Zurawski and de Vries, 1994; de Waal Malefyt et al., 1995).

CD4+ T cell clones with ThO, T h l and Th2 characteristics can produce IL-

13 (Zurawski and de Vries, 1994; de Waal Malefyt et al., 1995). N aive

produce IL-13 and IFNy but not IL-4 (Brinkmann and Kristofic, 1995).

After activation, IL-13 mRNA production can be detected within 2 hrs and

maximum production of the protein is reached by 6 hrs and continues for

at least 24 hrs but may continue to be produced for up to 7 days in some

conditions (Zurawski and de Vries, 1994; de Waal M alefyt et al., 1995). A

study of cytokine production in human tonsils found IL-13 localised to the

extrafoUicuIar, T cell rich area (Andersson et al., 1994).

Human B cells can synthesise IL-13. Expression of the IL-13 gene was

detected by RT-PCR analysis in both m ahgnant and EBV-transformed B

lymphocytes, (Fior et al., 1994), and small amounts of IL-13 protein an he

detected by ELISA in EBV culture supernatants (de Waal Malefyt et al., 1995).

M ast cells and basophils produce IL-13 when activated through their IgE

receptors (Burd et al., 1995; Li et al., 1996). Human bone marrow

mucosal-hke m ast cells constitutively express IL-13 but bone marrow

connective tissue-hke m ast cells require FceRI activation or IL-3 to induce

IL-13 production (Marietta et al., 1996). Murine bone marrow derived

m ast cells and human m ast cell hnes produce IL-13 in response to IgE or

64

Biological activity

IL-13 has no biological activity on T cells and T ceUs do not appear to express the 1L-13R (Zurawski and de Vries, 1994; de Waal Malefyt et al.,

1995). On the other hand IL-13 is a human B cell growth and

differentiation factor with very similar properties to that of lL-4. Like

lL-4, IL-13 win induce B cells from peripheral blood, spleen and tonsil to

increase the expression of a variety of surface antigens that include CD23, CD71, CD72, IgM, and MHC class 11 (Punnonen et al., 1993a;

Zurawski and de Vries, 1994; Defrance et al., 1994; M atthews et al., 1995).

Human B cell proliferation induced by anti-lgM, anti-CD40, or the CD40L

is enhanced by IL-13 (McKenzie et al., 1993; Cocks et al., 1993; Defrance et al., 1994; Banchereau et al., 1994a). IL-13 can support long term B cell growth when present with CD40L/L cell system (Gahbert et al., 1994;

Banchereau et al., 1994a). Comparisons of B ceU proliferation responses to

IL-13 found that signals via CD40 are more effective at supporting

proliferation than through slgM (McKenzie et al., 1993; Fluckiger et al.,

1994; Callard et al., 1996b).

In hum ans, IL-13 induces IgE production (McKenzie et al., 1993) and is a

switch factor for IgE and lgG4 (Punnonen et al., 1993a; Punnonen and de

Vries, 1994). B cells stim ulated by activated CD4+ T ceU clone B21 plus

1993b). Purified splenic or PBMC IgD+ B cells stim ulated by CD40L and

IL-13 produce IgM, IgG4 and IgE (Punnonen et al., 1993a; Cocks et al.,

1993). Immature human foetal bone marrow B cells (sp+, CD 10+, CD 19+)

have also been shown to produce IgM, IgG4 and IgE in response to IL-13

and activated CD4+ T ceUs or CD40L (Punnonen and de Vries, 1994).

Monocytes also respond to IL-13 by increasing the expression of MHC

class II, CD23 and various adhesion molecules (e.g. C D llb+ c, VLA-5,

CD 18 and CD29) but IL-13 inhibits the expression of Fc receptors CD 16,