TH2 CYTOKINES INDUCE REGIONALLY SPECIFIC ALTERATIONS IN GUT SMOOTH MUSCLE THAT ARE DEPENDENT UPON STAT6

TH2 CYTOKINES INDUCE REGIONALLY SPECIFIC ALTERATIONS IN GUT SMOOTH MUSCLE THAT ARE DEPENDENT UPON STAT6.

McDermott J, Zhao A, Gause W, Schopf L, Urban JF, Shea-Donohue T.

Department of Medicine and Microbiology, USUHS, Bethesda, MD.

The Th2 cytokines are induced by helminth infection. Worm expulsion is dependent upon IL-4 receptor (R) induced Stat6 activation. IL-4 and IL-13 share a receptor subunit, but IL-4 binds the type 1 and type 2 IL-4R and IL-13 binds only the type 2 IL-4R. Aim: To determine the role of Stat6 in IL-13 and IL-4induced changes in smooth muscle function in small intestine and colon. Method: Wild type Balb/c (WT) and Stat6 knockout (ko) mice were studied 7 days after injection with aIL-4:IL-4 complexes (IL-4C, days 0, 3, and 6) or IL-13 (day 0-6).Segments of mid-jejunum and colon were suspended longitudinally in organ baths and stretched to 9.9 mN (L₀). Concentration-dependent responses to acetylcholine (ACH, 10^-9-10^-3) and to ACH (10^-3) in the presence of tetrodotoxin (TTX) or the LTD₄ receptor antagonist, Wy,48252 (WY), to substance P (10^-3), and to KCl (60mM) were determined. Results: Within each region, responses to agonists were similar in untreated WT and Stat6ko mice. In the colon, IL-13 enhanced responses to ACH, substance P, and KCl in WT, but not in Stat6komice (table). IL-13 had no effect on ACH responses in the small intestine. In contrast, IL-4C increased responses to ACH (5.8 ± 1.6 versus 9.1 ± 0.5 N/cm²) and substance P (1.9 ± 0.3 versus 5.4 ± 2.1 N/cm²) in the small intestine in WT, but not in Stat6ko mice. IL-4 had no effect on ACH contractions in the colon. In both regions, cytokine-enhanced responses to ACH were blocked by TTX and completely inhibited by WY.

	WT	WT + IL-13	STAT6KO	STAT6KO + IL13
ACH	6.8 ± 0.9	10.8 ± 1.7^*	5.6 ± 0.4	5.6 ± 1.0
ACH + TTX	5.7 ± 0.7	5.1 ± 1.1	2.2 ± 1.6	1.7 ± 0.7
SP	3.2 ± 0.5	7.4 ± 0.6^*	3.4 ± 0.8	3.1 ± 0.3
KCl	3.2 ± 0.5	5.2 ± 0.9^*	1.9 ± 0.7	3.8 ± 1.0

Colon, ^* p< 0.05 vs. WT; values are maximum responses expressed as tension in N/cm²

Conclusions: Th2 cytokine-enhanced responses to cholinergic and tachykinin neurotransmitters are dependent on nerves and involve an LTD₄-mediated amplification of receptor-mediated Stat6 signaling pathways. The marked regional specificity of these cytokines suggests that IL-4 and IL-13 act preferentially at different sites to facilitate worm expulsion.

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